Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/06—Tripeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/07—Tetrapeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/545—Heterocyclic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers

Definitions

• PSMc* polystyrene-maleic anhydride
• active agents e.g., an aromatic-cationic peptide
• the present technology relates generally to aromatic-cationic peptide compositions where the aromatic-cationic peptide is conjugated to an acrylamido compound or phenyl- substituted maleimide compound and their use in the prevention and treatment of medical diseases and conditions.
• the present disclosure provides a composition comprising acrylamido compounds, phenyl-substituted maleimide compounds, derivatives, analogues, or
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH2.
• the present disclosure provides naturally or artificially occurring variants or analogues of acrylamido compounds or phenyl-substituted maleimide compounds or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*).
• the present disclosure provides a composition comprising Formula (III):
• Z is a substituted or unsubstituted aryl or heteroaryl group
• R 1 is H, OH or OPG
• R 4 and R 5 are independently H or a substituted or unsubstituted Ci_ 4 alkyl group or together form a carbonyl group;
• R 6 is H or a substituted or unsubstituted C 1 -C a 6 lkyl group
• cycloalkyl cycloalkylalkyl, alkenyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl group, or R 7 and R 8 , together with the nitrogen to which they are attached, form a heterocycle;
• PG is a hydroxyl protecting group and may be the same or different at each occurrence; alone or in combination with one or more active agents comprising an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2i and/or one or more aromatic-cationic peptides disclosed in Section III.
• the present disclosure provides a composition comprising Formula (IV):
• Z is a substituted or unsubstituted aryl or heteroaryl group
• R 1 is H, OH or OPG
• R 2 and R 3 are independently selected from H, OR 7 , OPG, halogen, CN, SO 2 NH 2 , NR 8 R 9 , OP(O)(OH) 2 , or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyalkyl group;
• R 7 , R 8 and R 9 are independently selected from H, a substituted or unsubstituted alkyl
• cycloalkyl cycloalkylalkyl, alkenyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl group, or R 7 and R 8 , together with the nitrogen to which they are attached, form a heterocycle;
• the present disclosure provides a composition comprising acrylamido compounds or phenyl-substituted maleimide compounds, derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
• the composition further comprises one or more additional active agents such as cyclosporine, a cardiac drug, an anti-inflammatory, an anti-hypertensive drug, an antibody, an ophthalmic drug, an antioxidant, a metal complexer, and an
• the present disclosure provides a method for treating or preventing mitochondrial permeability transition in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
• the present disclosure provides a method of treating a disease or condition characterized by mitochondrial permeability transition, comprising administering a therapeutically effective amount of a composition comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
• retinopathy cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration, oxygen-induced retinopathy, cardiomyopathy, ischemic heart disease, heart failure, hypertensive cardiomyopathy, vessel occlusion, vessel occlusion injury, myocardial infarction, coronary artery disease, or oxidative damage.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
• the removed organ comprises a heart, lung, pancreas, kidney, liver, or skin.
• the present disclosure provides a method for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising acrylamido compounds, phenyl- substituted maleimides, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg- 2'6'-Dmt-Lys-Phe-NH 2 .
• the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.
• the present disclosure provides a method of reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
• the present disclosure provides a method for treating or preventing no reflow following ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
• the present disclosure provides a method for preventing
• norepinephrine uptake in a subject in need of analgesia comprising administering to the subject an effective amount of a composition comprising acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic- cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
• the present disclosure provides a method for treating or preventing drug-induced peripheral neuropathy or hyperalgesia in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 .
• the present disclosure provides a method for inhibiting or suppressing pain in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic-cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
• the present disclosure provides a method for treating atherosclerotic renal vascular disease (ARVD) in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g. Ac* and/or PSMc*), alone or in combination with one or more active agents.
• the active agents include any one or more of the aromatic- cationic peptides shown in Section III.
• the aromatic-cationic peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 . .
• the composition comprises acrylamido compounds, phenyl- substituted maleimide compounds, derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*).
• the composition further comprises one or more of at least one pharmaceutically acceptable pH-lowering agent; and at least one absorption enhancer effective to promote bioavailability of the active agent, and one or more lamination layers.
• compositions comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound, as well as methods for their use.
• Such molecules are referred to hereinafter as "peptide conjugates.”
• At least one acrylamido compound and/or Ac* compound or phenyl-substituted maleimide compound and/or PSMc* compound, and at least one aromatic-cationic peptide associate to form a peptide conjugate.
• the acrylamido compound and/or Ac* compound or phenyl- substituted maleimide compound and/or PSMc* compound and aromatic-cationic peptide can associate by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds. Chemical bonds include, for example, covalent bonds and coordinate bonds. Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking. In some embodiments, the peptide conjugates have the general structure shown below: aromatic-cationic peptide-acrylamido compound aromatic-cationic peptide-phenyl-substituted maleimide compound
• the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-acrylamido compound aromatic-cationic peptide-linker-phenyl-substituted maleimide compound aromatic-cationic peptide-linker-Ac* compound aromatic-cationic peptide-linker-PSMc* compound
• the present technology provides a peptide conjugate comprising an acrylamido compound and/or Ac* compound, wherein the aromatic-cationic peptide is selected from the group consisting of: Phe-D-Arg-Phe-Lys-NH 2 , D-Arg-2'6'-Dmt-Lys-Phe- NH 2 , 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , or any peptide described in Section III; and wherein the acrylamido compound is selected from the group consisting of: (E)-3-(3- Hydroxy-4-methoxy-phenyl)-N-naphthalen- 1 -yl-acrylamide, (E)-N-(2-Benzyloxy-phenyl)-3- (3 -hydroxy-4-methoxy-phenyl)-acrylamide, (E)-3 -(3 -Hydroxy-4-methoxy-phenyl)-N
• the present technology provides a peptide conjugate comprising a phenyl-substituted maleimide compound and/or PSMc* compound, wherein the aromatic- cationic peptide is selected from the group consisting of: Phe-D-Arg-Phe-Lys-NH 2 , D-Arg- 2'6'-Dmt-Lys-Phe-NH 2 , 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , or any peptide described in Section III; and wherein the phenyl-substituted maleimide compound is selected from the group consisting of: l-(5-chloro-2-methoxyphenyl)-3-phenyl-pyrrole-2,5-dione, l-(4- trifluoromethoxyphenyl)-3-phenyl-pyrrole-2,5-dione, l-(3-trifluoromethylpheny
• the acrylamido compound and/or Ac* compound or phenyl- substituted maleimide compound and/or PSMc* compound is conjugated to the aromatic- cationic peptide by a linker.
• the acrylamido compound and/or Ac* compound or phenyl-substituted maleimide compound and/or PSMc* compound and aromatic-cationic peptide are chemically bonded.
• the acrylamido compound and/or Ac* compound or phenyl-substituted maleimide compound and/or PSMc* compound and aromatic-cationic peptide are physically bonded.
• the acrylamido compound and/or Ac* compound or phenyl- substituted maleimide compound and/or PSMc* compound is conjugated to the aromatic- cationic peptide by a linker.
• the acrylamido compound and/or Ac* compound or phenyl-substituted maleimide compound and/or PSMc* compound and aromatic-cationic peptide are chemically bonded.
• the the acrylamido compound and/or Ac* compound or phenyl-substituted maleimide compound and/or PSMc* compound and aromatic-cationic peptide are physically bonded.
• Alzheimer's disease Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease,
• the subject is suffering from ischemia or has an anatomic zone of no-reflow in one or more of cardiovascular tissue, skeletal muscle tissue, cerebral tissue and renal tissue.
• the present technology provides methods for reducing CD36 expression in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• the present technology provides methods for treating, ameliorating or preventing a medical disease or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• the subject is diagnosed as having, is suspected of having, or at risk of having atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's disease, diabetes, diabetic nephropathy, or obesity.
• ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's disease, diabetes, diabetic nephropathy, or obesity.
• the present technology provides methods for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.
• the present technology provides methods for reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• the neurodegenerative diseases comprise
• Alzheimer's disease Parkinson's disease, or ALS.
• the present technology provides methods for preventing or treating a burn injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• the present technology provides methods for preventing norepinephrine uptake in a subject in need of analgesia, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• the present technology provides methods for treating,
• ameliorating or preventing drug-induced peripheral neuropathy or hyperalgesia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• the present technology provides methods for inhibiting or suppressing pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• the present technology provides methods for treating
• Atherosclerotic renal vascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• ARVD atherosclerotic renal vascular disease
• the aromatic-cationic peptide is defined by Formula A.
• halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
• R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
• the peptide is defined by Formula B:
• R 1 and R 2 are each independently selected from
• R ⁇ R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from (i) hydrogen;
• halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; and n is 4.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; R 8 and R 12 are methyl; R 10 is hydroxyl; and n is 4.
• the aromatic-cationic peptides of the present technology have a core structural motif of alternating aromatic and cationic amino acids.
• the peptide may be a tetrapeptide defined by any of Formulas C to F set forth below:
• aromatic is a residue selected from the group consisting of: Phe (F), Tyr (Y), Trp (W), and Cyclohexylalanine (Cha); and Cationic is a residue selected from the group consisting of: Arg (R), Lys (K), Norleucine (Nle), and 2-amino-heptanoic acid (Ahe).
• Figure 1 shows an illustrative example of an aromatic-cationic peptide of the present disclosure linked by a labile bond to an acrylamido compound and/or Ac* compound.
• Figure 2 shows an illustrative example of an aromatic-cationic peptide of the present disclosure linked by a labile bond to a phenyl-substituted maleimide compound and/or PSMc* compound.
• Figure 3 shows illustrative examples of aromatic-cationic peptides of the present disclosure linked by covalent attachment to self-immolating moieties.
• Figures 4A and 4B show illustrative examples of aromatic-cationic peptides of the present disclosure incorporating spacer units to link the additional moieties to the peptide.
• Figure 5 shows illustrative peptide chemistry to form amide bonds, where the R 2 free amine is D-Arg-2'6'-Dmt-Lys-Phe-NH 2 and Ri is selected from a linker bearing the formula:— (linker)— COOH; or where linker consists of one or more carbon atoms. In some embodiments, the linker consists of two or more carbon atoms.
• Figures 6A and 6B show exemplary linking chemistry of the present disclosure.
• R is an arcylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound containing a pendant COOH group and R' is a linker bearing the formula:— (linker)— OH where linker consists of at least one or more carbon atoms.
• R is a linker bearing the formula:— (linker)— COOH where linker consists of at least one or more carbon atoms; and R' is a an arcylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound containing a pendant OH group.
• Figure 7 shows exemplary, non-limiting chemical structures of the disclosed acrylamido compounds (1)-(146) of the present technology.
• compositions comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound and/or Ac* compound or a phenyl-substituted maleimide compound and/or PSMc* compound.
• Such molecules are referred to hereinafter as peptide conjugates.
• At least one acrylamido compound and/or Ac* compound as described in Section I or at least one phenyl-substituted maleimide compound and/or PSMc* compound as described in Section II and at least one aromatic-cationic peptide as described in Section III associate to form a peptide conjugate.
• the acrylamido compound and/or Ac* compound or phenyl-substituted maleimide compound and/or PSMc* compound and aromatic-cationic peptide can associate by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds. Chemical bonds include, for example, covalent bonds and coordinate bonds. Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking.
• the peptide conjugates have the general structure shown below: aromatic-cationic peptide-acrylamido compound aromatic-cationic peptide-phenyl-substituted maleimide compound
• the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-acrylamido compound aromatic-cationic peptide-linker-phenyl-substituted maleimide compound aromatic-cationic peptide-linker-Ac* compound aromatic-cationic peptide-linker-PSMc* compound
• the peptide conjugates described herein can occur and can be used as the neutral (non-salt) peptide conjugate, the description is intended to embrace all salts of the peptide conjugates described herein, as well as methods of using such salts of the peptide conjugates.
• the salts of the peptide conjugates comprise
• Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound).
• the desired salt of a basic peptide conjugate may be prepared by methods known to those of skill in the art by treating the compound with an acid.
• inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
• organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid.
• Salts of basic peptide conjugates with amino acids such as aspartate salts and glutamate salts, can also be prepared.
• the desired salt of an acidic peptide conjugate can be prepared by methods known to those of skill in the art by treating the compound with a base.
• inorganic salts of acid conjugates include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts.
• organic salts of acid peptide conjugates include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, ⁇ , ⁇ '-dibenzylethylenediamine, and
• salts of acidic peptide conjugates with amino acids can also be prepared.
• the present technology also includes all stereoisomers and geometric isomers of the peptide conjugates, including diastereomers, enantiomers, and cis/trans (E/Z) isomers.
• the present technology also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures.
• references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
• an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
• Compounds comprising radioisotopes such as tritium, C 14 , P 32 and S 35 are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.
• the term "about” encompasses the range of experimental error that may occur in a measurement and will be clear to the skilled artisan. If there is an ambiguity, the term is construed to mean +/- 10%.
• “Ac*” collectively refers to derivatives, variants or analogues of the acrylamido compounds of the present technology, such as but not limited to Formula (III), Formula (IIIA), Formula (IIIB), Formula (IIIC), Formula (HID), Formula (IV) or Formula (IV A), stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof.
• the "administration" of an agent, drug, or peptide to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or
• heterocyclylalkyl or heterocyclyl group as defined herein.
• Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
• the amide is -NR a C(O)-(C 1-5 alkyl) and the group is termed
• amidine refers to -C(NR c )NR d R e and -NR c C(NR d )R e , wherein R c , R d , and R e are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
• amine refers to -NR f R g groups, wherein R f and R g are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
• the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino.
• the amine is NH 2 , methylamino, dimethy lamino, ethylamino, diethylamino, propylamino, isopropy lamino, phenylamino, or benzylamino.
• Amino acid analogues refer to compounds that have the same basic chemical structure as a naturally-occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
• Such analogues have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally-occurring amino acid.
• Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally- occurring amino acid. Amino acids can be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
• (C 1 -C 3 )alkyl or “(C 1 -C 3 )alkoxy” refer to any group such as methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy and isopropoxy.
• ( C 1 -C 6 )alkyl refer, unless otherwise provided, to any straight or branched C 1 -C 6 alkyl group, hence comprehensive of the aforementioned "(C 1 -C 3 )alkyl” group and also comprising n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
• (C 1 -C 2 )haloalkoxy refers to a (C 1 -C 2 )alkoxy group substituted at the carbon atoms with one or more halogen atoms.
• groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2- chloroethoxy, l-fluoro-2,2,-dichloroethoxy, and the like.
• (C 1 -C 2 )Ch 1 a-lCo 2 alkyl refers to a C 1 -C 2 haloalkyl group, such as CF 3 .
• control is an alternative sample used in an experiment for comparison purpose.
• a control can be "positive” or “negative.”
• a positive control a compound or composition known to exhibit the desired therapeutic effect
• a negative control a subject or a sample that does not receive the therapy or receives a placebo
• the term "effective amount" refers to a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g., an amount which results in the prevention of, or a decrease in a disease or disorder or one or more signs or symptoms associated with a disease or disorder.
• the amount of a composition administered to the subject will depend on the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
• the compositions can also be administered in combination with one or more additional therapeutic compounds.
• the therapeutic compounds may be administered to a subject having one or more signs or symptoms of a disease or disorder.
• ester refers to -C(O)OR m groups.
• R m is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
• the term ester also refers to -OC(O)R m groups.
• an ester may be -OC(O)-alkyl, -OC(O)-aryl, or -OC(O)-aralkyl, wherein each alkyl, aryl, or aralkyl group is substituted or unsubstituted.
• halogen refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
• heterocyclyloxy refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
• heteroaryloxy as used herein are defined analogously to “aryloxy” and “aralkoxy.”
• hydrazine refers to -NR r NR s R t groups where R r , R s , and R t are each independently selected from H or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
• hydroxy or "hydroxyl” as used herein can refer to -OH or its ionized form, -O .
• hydroxylamine refers to -NR u OH groups
• alkoxyamine refers to -NR u O(alkyl) groups, where R u is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
• aralkoxyamines refers to -NR u O(aralkyl) groups.
• imide refers to -C(O)NR v C(O)R w , wherein R v and R w are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
• the term "imine” as used herein refers to -CR x (NR y ) and -N(CR x R y ) groups, wherein R x and R y are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R x and R y are not both simultaneously hydrogen.
• an "isolated” or “purified” polypeptide or peptide is substantially free of cellular material or other contaminating polypeptides from the cell or tissue source from which the agent is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized.
• an isolated aromatic-cationic peptide would be free of materials that would interfere with diagnostic or therapeutic uses of the agent.
• interfering materials may include enzymes, hormones and other proteinaceous and nonproteinaceous solutes.
• leaving group has the same meaning to one skilled in the art (Jerry March, Advanced Organic Chemistry: Reactions, mechanisms and structure— 3d Edition, John Wiley and Sons Ed.; 1985, page 179) and represents a group which is part of and attached to a substrate molecule; in a reaction where the substrate molecule undergoes a displacement reaction (for example with a nucleophile), the leaving group is then displaced.
• leaving groups are halogens, sulfonic esters, such as p-toluenesulfonate, p- bromobenzenesulfonate, p-nitrobenzenesulfonate, methanesulfonate,
• net charge refers to the balance of the number of positive charges and the number of negative charges carried by the amino acids present in the aromatic-cationic peptides of the present technology. In this specification, it is understood that net charges are measured at physiological pH.
• the naturally occurring amino acids that are positively charged at physiological pH include L-lysine, L-arginine, and L-histidine.
• the naturally occurring amino acids that are negatively charged at physiological pH include L- aspartic acid and L-glutamic acid.
• nitrile or "cyano” as used herein refers to the -CN group.
• nitro refers to an -NO 2 group.
• non-naturally-occurring refers to a composition which is not found in this form in nature.
• a non-naturally-occurring composition can be derived from a naturally-occurring composition, e.g., as non-limiting examples, via purification, isolation, concentration, chemical modification (e.g., addition or removal of a chemical group), and/or, in the case of mixtures, addition or removal of ingredients or compounds.
• a non-naturally-occurring composition can comprise or be derived from a non-naturally- occurring combination of naturally-occurring compositions.
• a non-naturally-occurring composition can comprise a mixture of purified, isolated, modified and/or concentrated naturally-occurring compositions, and/or can comprise a mixture of naturally-occurring compositions in forms, concentrations, ratios and/or levels of purity not found in nature.
• pharmaceutically acceptable salts means a salt prepared from a base or an acid which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime).
• pharmaceutically acceptable inorganic acids include salts of boric, carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamic and sulfuric acids.
• Salts derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxyl acids (e.g., citric, gluconic, glycolic, lactic, lactobionic, malic, and tartaric acids), aliphatic monocarboxylic acids (e.g., formic, acetic, proprionic, butyric, isobutyric, 2,2-dichloroacetic acid, trifluoroacetic, capric (decanoic), caproic (hexanoic), caprylic (octanoic), palmitic, lauric, oleic, undecylenic and stearic acids), amino acids (e.g., aspartic and glutamic acids), aromatic carboxylic acids (e.g.
• ethanesulfonic 2-hydroxyethanesulfonic acid, ethane- 1 ,2-disulfonic acid, isethionic, methanesulfonic, naphthalene- 1, 5 -disulfonic, naphthalene -2, 6-disulfonic, naphthalene-2- sulfonic acid, and p-toluenesulfonic acids), xinafoic acid, and the like.
• the salt is an acetate salt, a trifluoroacetate salt or a hydrochloride salt. In some embodiments, the salt is a tartrate salt.
• polyfluorinated alkyl or “polyfluorinated alkoxy” refer to any straight or branched C 1 -C 6 alkyl or alkoxy group as defined above, wherein more than one hydrogen atom is replaced by fluorine atoms such as, for instance, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1 ,2-difluoroethyl, l,l,l ,3,3,3-hexafluoropropyl-2- yl, and the like.
• polypeptide As used herein, the terms "polypeptide,” “peptide,” and “protein” are used interchangeably herein to mean a polymer comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
• Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins.
• Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
• Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art.
• prevention or “preventing” of a disease or medical condition refers to a compound that, in a statistical sample, reduces the occurrence of the disease or medical condition in the treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of the disease or medical condition relative to the untreated control sample.
• prodrug refers to less than fully active compounds that are rapidly transformed in vivo to yield a fully active therapeutic, for example by hydrolysis of an ester.
• a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, 1975; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
• protecting group refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 3rd Ed. (John Wiley & Sons, Inc., New York).
• PSMc* collectively refers to derivatives, variants or analogues of the phenyl-substituted maleimide compounds of the present technology, such as but not limited to Formula (IV) or Formula (IV A), stereoisomers thereof, tautomers thereof, solvates thereof, and pharmaceutically acceptable salts thereof.
• the term “separate” therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes.
• sequential therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case.
• the terms "subject,” “individual,” or “patient” can be an individual organism, a vertebrate, a mammal, or a human.
• substituted refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms.
• Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
• a substituted group is substituted with one or more substituents, unless otherwise specified.
• a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents.
• substituent groups include: halogens (i.e., F, CI, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heteroaryloxy and heteroaralkoxy groups; heterocyclyloxy, and
• heterocyclylalkoxy groups carbonyls (oxo); carboxyls; alkanoyl and alkanoyloxy groups; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides (i.e., -N 3 ); amides; ureas; amidines; guanidines; enamines; imides; imines; nitro groups; nitriles (i.e., CN); and the like.
• Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.
• Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
• Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems.
• aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl,
• aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups.
• the aryl groups are phenyl or naphthyl.
• aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
• aryl groups also includes substituted aryl groups. Groups such as tolyl are referred to as substituted aryl groups.
• substituted aryl groups may be mono- substituted or substituted more than once.
• monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
• the aryl group is phenyl, which can be substituted or unsubstituted.
• substituted phenyl groups have one or two substituents.
• substituted phenyl groups have one substituent.
• Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
• aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms.
• Aralkyl groups may be substituted or unsubstituted. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group.
• Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl.
• Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.
• Heterocyclyl groups are non-aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
• the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms.
• heterocyclyl groups include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members.
• Heterocyclyl groups encompass partially unsaturated and saturated ring systems, such as, for example, imidazolinyl and imidazolidinyl groups.
• the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidinyl.
• the phrase also includes heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members, referred to as "substituted heterocyclyl groups".
• Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl,
• substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.
• the heteroatom(s) can also be in oxidized form, if chemically possible.
• Heteroaryl groups are aromatic rings or ring systems containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
• the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms.
• heterocyclyl groups include mono-, bi- and tricyclic rings having 5 to 16 ring members, whereas other such groups have 5 to 6, 5 to 10, 5 to 12, or 5 to 14 ring members.
• Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl,
• Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3-dihydro indolyl groups.
• Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group.
• Representative heterocyclyl alkyl groups include, but are not limited to, morpholin-4-yl-ethyl, and tetrahydrofuran-2-yl-ethyl.
• Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.
• the heteroatom(s) can also be in oxidized form, if chemically possible.
• Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
• Heteroaralkyl may be substituted or unsubstituted.
• Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group.
• Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above.
• the heteroatom(s) can also be in oxidized form, if chemically possible.
• Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above.
• linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
• branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
• cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
• Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.
• the term "sulfonamido" includes S- and N-sulfonamide groups, i.e., -SO 2 NR dd R ee and -NR dd SO 2 R ee groups, respectively.
• R dd and R ee are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,
• a "synergistic therapeutic effect” refers to a greater-than-additive therapeutic effect which is produced by a combination of at least two agents, and which exceeds that which would otherwise result from the individual administration of agents. For example, lower doses of one or more agents may be used in treating a disease or disorder, resulting in increased therapeutic efficacy and decreased side-effects.
• a "therapeutically effective amount" of a compound refers to compound levels in which the physiological effects of a disease or disorder are, at a minimum, ameliorated.
• a therapeutically effective amount can be given in one or more administrations.
• the amount of a compound which constitutes a therapeutically effective amount will vary depending on the compound, the disorder and its severity, and the general health, age, sex, body weight and tolerance to drugs of the subject to be treated, but can be determined routinely by one of ordinary skill in the art.
• thiol refers to–SH groups, while sulfides include–SR ff groups, sulfoxides include–S(O)R gg groups, sulfones include -SO 2 R hh groups, and sulfonyls include –SO 2 OR ii .
• R ff , R gg , R hh , and R ii are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
• the sulfide is an alkylthio group, -S-alkyl.
• Treating” or“treatment” as used herein covers the treatment of a disease or medical condition described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disorder; (iii) slowing progression of the disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or medical condition.
• urea refers to -NR*-C(O)-NR kk R mm groups.
• R jj , R tt , and R mm groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
• the compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
• Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.
• alkyl polyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkyl-heteroaryl, heteroaryl-alkyl, amino-alkyl, amino groups and derivatives thereof, such as, for instance, alkylamino, dialkylamino, arylamino, diarylamino, ureido, alkylureido or arylureido;
• sulfurated derivatives such as, for instance, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfmyl, arylsulfmyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or
• each of the above substituents may be further substituted by one or more of the aforementioned groups.
• any group whose name has been identified as a composite name such as, for instance, cycloalkylalkyl, arylalkyl, heteroarylalkyl, alkylheteroaryl, (Ci-C3)alkoxyalkyl, alkylthio, arylthio, amino-alkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylureido, arylureido,
• alkylcarbonylamino alkenylcarbonylamino, arylcarbonylamino, aryloxy, arylalkyloxy, alkylcarbonyloxy, alkoxy carbonylamino; heteroaryloxy, arylcarbonyloxy,
• alkylideneaminoxy alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfmyl, arylsulfmyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl and the like, has to be intended as conventionally construed from the parts to which they derive.
• alkoxycarbonyl stands for a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical.
• the present technology provides compounds that, by way of example but not by way of limitation, inhibit, ameliorate, or prevent medical diseases or conditions, and that are useful as therapeutic and/or prophylactic agents to treat or prevent medical diseases and conditions.
• a compound of Formula (I) is provided.
• Compounds of Formula (I) can be used alone or in combination with or conjugated to one or more active agents (e.g., an aromatic-cationic peptide of Section III), or other active agent to treat, prevent, or ameliorate a disease or condition.
• Figure 7 shows exemplary, non-limiting chemical structures of the disclosed acrylamido compounds (1)-(146) of the present technology.
• Formula (I) is shown below:
• W is aryl or heteroaryl; a is 0, 1, 2, or 3;
• R and R are the same or different and, independently from each other, are selected from: hydrogen; halogen; (C 1 -C 3 )alkoxy; (C 1 -C2)haloalkoxy; (C 1 -C 2 )haloalkyl; NRiR 2 ; CN;
• R" is independently selected from: halogen; (C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy; (C 1 -C 3 )alkoxyalkyl; (C 1 -C 2 )haloalkoxy; (C 1 - C 2 )haloalkyl; NR 3 R 4 ; or (CH 2 ) classroom— X— (CH 2 ) m — Q; wherein: n, m are independently 0, 1, or 2; X is a direct bond; O; S; NH; N(C 1 -C 3 )alkyl;
• Q is an optionally substituted aryl, heteroaryl, heterocycloalkyl or cycloalkyl;
• R 1 , R 2 , R 3 , and R 4 are the same or different and, independently from each other, are a hydrogen atom; a (C 1 -C 3 )alkyl or, taken together with the nitrogen atom to which they are attached, Ri— N— R 2 and R 3 — N— R 4 may form a heterocyclic ring of formula:
• R 5 is a hydrogen atom or a (C 1 -C 3 )alkyl group; with the proviso that: when W is phenyl, a is not 0; when W is phenyl and R is hydrogen, R" is other than chlorine, methyl, isopropyl, CF 3 or NH 2 ; when W is indazol-5-yl or pyrid-2-yl, R is other than hydrogen, (C 1 -C 3 )alkoxy; as well as its isomers, tautomers, racemic forms, enantiomers, diastereomers, epimers, polymorphs, mixtures thereof, prodrugs, and the pharmaceutically acceptable salts thereof.
• the present technology provides compounds of general Formula (I), as defined above, as well as their isomers, racemic forms, tautomers, enantiomers, diastereomers, epimers, polymorphs, mixtures thereof, prodrugs and the pharmaceutically acceptable salts thereof, for use in treatment of diseases and conditions.
• the present technology also relates to the pharmaceutical compositions containing one or more compounds of general Formula (I), as defined above, and/or prodrugs, and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
• the acid-addition salts may be prepared by separately reacting the purified compound in its purified form with an organic or mineral acid and isolating the salt thus formed.
• the resulting salts are, for example, hydrochlorides, hydrobromides, sulfates, hydrogenosulfates, dihydrogenophosphates, citrates, maleates, fumarates, trifluoroacetates, 2- naphtalenesulfonates, para-toluenesulfonates .
• the present technology also relates to the all the isomers and their admixtures, tautomeric forms, racemic forms, enantiomers, diastereoisomers, epimers, as well as their crystalline forms, including their polymorphic forms, and mixtures thereof.
• each form is contemplated as being included within the present technology whether existing in equilibrium or predominantly in one form.
• the present technology is directed not only to racemic mixtures of these
• the metabolites and the pharmaceutically acceptable bio-precursors (otherwise referred to as prodrugs) of the compounds of Formula (I) are included within the scope of, and suitable for use in, the present technology.
• prodrugs of the compounds of Formula (I) are also within the scope of the present technology.
• a “prodrug” is a compound which is metabolically converted to a therapeutically active compound after administration.
• the term “prodrug” should be interpreted as broadly herein as is generally understood in the art. While not intending to limit the scope of the present technology, conversion may occur by in vivo hydrolysis of biologically labile groups. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
• certain derivatives of compounds of Formula (I) which may have little or no pharmacological activity themselves can, when administered into the body, be converted into compounds of Formula (I) having the desired activity, for example, by hydro lytic cleavage.
• Prodrugs in accordance with the present technology can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula (I) with certain moieties known to those skilled in the art as pro-moieties as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985) or in Prodrugs: Design and clinical applications by Jarkko Rautio et al., Nature Reviews Drug Discovery, Vol. 7: 255-270 (2008).
• Non limiting examples of prodrugs include: a carboxylic ester of a phenolic moiety of compounds of Formula (I); a phosphate ester of a phenolic moiety of compounds of Formula (I); a phosphonooxymethyl ether of a phenolic moiety of compounds of Formula (I); a carbamate derivative a phenolic moiety of compounds of Formula (I).
• prodrugs are a carboxylic or a phosphate ester of a phenolic moiety of compounds of Formula (I). While not intending to be limiting, an ester may be an alkyl ester, an aryl ester, a heteroaryl ester or an inorganic ester.
• the present technology provides acrylamido derivatives of Formula (I), wherein:
• W is a phenyl ring substituted by 1 or 2 groups R";
• R is halogen; (C 1 -C 3 )alkoxy; (C 1 -C 3 )alkyl;
• R is hydrogen
• n 0 or 1 ;
• n 0 or 1 ;
• X is O; S; NH; N(Cl-C3)alkyl;
• Q is aryl or heteroaryl.
• R is fluorine; methoxy; methyl
• R" is halogen or (CH 2 ) n — X— (CH 2 ) m — Q, wherein:
• n and m are chosen in a way that their sum (n+m) is equal to 1 ;
• Q is aryl or heteroaryl
• the present technology provides acrylamido derivatives of Formula (I), wherein:
• W is a bicyclic aryl or a bicyclic heteroaryl ring, optionally substituted by 1 or 2 groups R";
• R is halogen; (C 1 -C 3 )alkoxy; (C 1 -C 3 )alkyl;
• n 0 or 1 ;
• X is O; S; NH; N(Cl-C3)alkyl;
• Q is aryl or heteroaryl.
• W is a bicyclic aryl or a bicyclic heteroaryl ring, unsubstituted or substituted by one group (CH 2 ) n — X— (CH 2 ) m — Q, wherein: n and m are chosen in a way that their sum (n+m) is equal to 1 ;
• X is O
• R" selected from chlorine; bromine; (C 1 - C 2 )haloalkyl; 4-(C 1 -C 3 )alkylpiperazin-l-yl;
• R is fluorine; methoxy; methyl; as well as its isomers, tautomers, racemic forms,
• a compound of Formula (I) useful for the prevention and/or treatment of diseases is one or more selected from the group consisting of:
• R 1 , R 2 , R 3 , and R 4 each independently represents: hydrogen; halo; hydroxy; (C 1 -C 6 ) alkyl optionally substituted by hydroxy or (C 1 -C 4 ) alkoxy; (C 1 -C 6 ) haloalkyl; (C 1 -C 6 ) alkoxy; and (C 1 -C 6 ) haloalkoxy.
• the diseases result from opening of the MPTP which are characterized by degenerative tissue damages, such as diabetes and diabetic complications, neurological diseases and stroke, heart infarction, inherited dystrophies, and hepatitis.
• Another aspect of the present technology is to provide a method of preventing and/or treating diseases resulting from opening of the MPTP which are characterized by degenerative tissue damages, including, diabetes and diabetic complications, neurological diseases and stroke, heart infarction, inherited dystrophies and hepatitis by administering to a subject suffering from any such diseases an effective amount of a compound of Formula (II) as defined above.
• a group of compounds of Formula (II) useful for the prevention and/or treatment of diseases is represented by compounds of Formula (II) wherein: R 1 , R 2 , R 3 , and R4 each independently represents: hydrogen; halo; hydroxy; (C 1 -C 4 ) alkyl optionally substituted by hydroxy or (C 1 -C 4 ) alkoxy; (C 1 -C 4 ) haloalkyl; (C 1 -C 4 ) alkoxy; and (C 1 -C 4 ) haloalkoxy.
• R 1 , R 2 , R 3 , and R 4 each independently represents: hydrogen; fluoro; chloro; bromo; hydroxy; (C 1 -C4) alkyl optionally substituted by hydroxy or (C1-C2) alkoxy; CF 3 ; CC1 3 ; methoxy; ethoxy; isopropoxy; OCF 3 ; OCHF 2 ; and OCH 2 F.
• the terms "(C 1 -C 6 ) alkyl”, “(C 1 -C 6 ) haloalkyl”, “(C 1 -C 6 ) alkoxy”, “(C 1 -C 6 ) haloalkoxy”, “(C1-C4) alkyl”, “(C1-C4) haloalkyl”, “(C1-C4) alkoxy” and “(C1-C4) haloalkoxy” are intended to include both branched and straight alkyl chains.
• the branched alkyl moieties of the above radicals may contain one or more asymmetric carbon atoms which may give rise to enantiomers and/or diastereoisomers.
• stereoisomers is herein intended all isomers of individual molecules that differ only in the configuration of their carbon atoms in the space. This term includes enantiomers and diastereoisomers.
• the present technology includes all the possible stereoisomers of the compounds of Formula (II) both as single isomers and their mixtures, including racemates. Some crystalline forms of the compounds may exist as polymorphs, which are also included in the present technology. Some of the compounds are solvated with water, and as such they are also intended to be encompassed within the scope of the present technology.
• a compound of Formula (II) useful for the prevention and/or treatment of diseases includes one or more compounds selected from the group consisting of:
• the present technology provides compounds of Formula (III):
• Z is a substituted or unsubstituted aryl or heteroaryl group
• R 1 is H, OH or OPG
• R 2 and R 3 are independently selected from H, OR 7 , OPG, halogen, CN, SO 2 NH 2 , NR 8 R 9 , OP(O)(OH) 2 , or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyalkyl group;
• R 4 and R 5 are independently H or a substituted or unsubstituted Ci_ 4 alkyl group or together form a carbonyl group;
• R 7 , R 8 and R 9 are independently selected from H, a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl group, or R 7 and R 8 , together with the nitrogen to which they are attached, form a heterocycle; and PG is a hydroxyl protecting group and may be the same or different at each occurrence.
• compounds of Formula (III) have the structure of Formula (OA):
• compounds of Formula (III) have the structure of Formula (OB):
• compounds of Formula (III) have the structure of Formula (IIID):
• R 4 and R 5 together form a carbonyl group
• compounds of Formula (III) have the structure of Formula (IV):
• Z and R 1 , R 2 and R 3 may be defined as described herein for any of Formulas (III), (IIIA), (IIIB), (IIIC), or (IIID).
• compounds of Formula (IV) have the structure of Formula (IVA):
• each of the variables R 1 , R 2 , R 3 , R 10 , R 11 , R 12 , X 1 , X 2 , X 3 , X 4 , and X 5 may be defined as described herein for any of Formulas (III), (IIIA), (IIIB), (IIIC), (HID) or (IV) containing said variables.
• R 1 is OH.
• R 2 and R 3 are independently selected from H, F, CI, Br, CN, or a substituted or unsubstituted alkyl or alkoxy group.
• R 2 is H, F, CN, NH 2 , SO 2 NH 2 , OP(O)(OH) 2 (or a salt thereof, e.g., a sodium salt) or a Ci_ 4 akyl or Ci_ 4 alkoxy group, optionally substituted with one or more halogens.
• R 2 is H, halogen, CN, NH 2 , SO 2 NH 2 ,
• R 1 is OH.
• R 2 is F, CI, or a Ci_ 4 alkoxy group.
• R 1 is H and R 2 is a halogen.
• R 1 is H, R 2 is a halogen and R 3 is a halogen or a Ci_ 4 akyl or Ci_ 4 alkoxy group, optionally substituted with one or more halogens.
• R 4 and R 5 are H.
• R 6 is H.
• Z is an aryl or heteroaryl group (e.g., phenyl, naphthyl, iH-indenyl, 2,3-dihydro-iH-indenyl, pyridinyl, pyrimidinyl, indolyl, benzimidazolyl, benzodioxolyl, benzoxazolyl, indazolyl, or benzotriazolyl group) substituted with one or more (e.g., 1, 2, 3, or 4) halogen, -(Co_6 alkyl)- OR 13 -(Co-6 alkyl)-SR 13 NR 14 R 15 , or a substituted or unsubstituted alkyl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl group, wherein R 13 is selected from a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl group,
• Z is a phenyl, naphthyl, pyridinyl, indolyl, indazolyl, benzotriazolyl, or benzimidazolyl group substituted with 1 or 2 substituents selected from F, Cl, Br, I, -(C 0-6 alkyl)-OR 13 , -(C 0-6 alkyl)-SR 13 , N-methylpiperidinyl, 4-methylpiperazinyl, CF 3 , NR 14 R 15 , benzyl, oxazolyl, or an unsubstituted C 1-6 alkyl group, wherein R 13 , R 14 , and R 15 are as defined before.
• X 3 is N.
• X 5 is N and is substituted with R 10 .
• R 12 is F, Cl, Br, I, -(C 0-6 alkyl)-OR 13 , -(C 0-6 alkyl)-SR 13 , or NR 14 R 15 .
• R 12 is OR 13 or CH 2 OR 13 or SR 13 .
• R 13 is substituted with one or more substituents selected from F, Cl, Br, I, a unsubstituted C 1-6 alkyl, trifluoromethyl, imidazolyl, 4-methylimdiazolyl, N-methylimidazolyl, piperidinyl, N- methylpiperidinyl, N-methylpiperidinyloxy, piperidinyloxy, piperidinylmethyl, N- methylpiperazinyl, N-methylpiperazinylmethyl, pyrrolidinyl, N-methylpyrazolylmethyl, 1,3- dimethylpyrazolylmethyl, or morpholinylmethyl.
• substituents selected from F, Cl, Br, I, a unsubstituted C 1-6 alkyl, trifluoromethyl, imidazolyl, 4-methylimdiazolyl, N-methylimidazolyl, piperidinyl, N- methylpiperidinyl, N-methylpiperidinyloxy, piperidinyl
• the phenyl when Z is phenyl, the phenyl bears at least one substituent other than H. In some embodiments of compounds of Formula (IIIC), when Z is phenyl and R 2 is H, Z bears at least one substituent other than Cl, methyl, isopropyl, CF 3 , or NH 2 .
• aromatic-cationic peptides of the present technology are water-soluble, highly polar, and can readily penetrate cell membranes.
• the aromatic-cationic peptides of the present technology include a minimum of three amino acids, covalently joined by peptide bonds.
• the maximum number of amino acids present in the aromatic-cationic peptides of the present technology is about twenty amino acids covalently joined by peptide bonds. In some embodiments, the maximum number of amino acids is about twelve. In some embodiments, the maximum number of amino acids is about nine. In some embodiments, the maximum number of amino acids is about six. In some embodiments, the maximum number of amino acids is four.
• the present technology provides an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof such as acetate salt or trifluoroacetate salt.
• the peptide comprises at least one net positive charge; a minimum of three amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1 ; and
• the peptide comprises the amino acid sequence Phe-D-Arg- Phe-Lys-NH 2 or D-Arg-2'6'-Dmt-Lys-Phe-NH 2 . In some embodiments, the peptide comprises one or more of the peptides of Table A:
• R 1 and R 2 are each independently selected from
• R are each independently selected from
• halogen encompasses chloro, fluoro, bromo, and iodo
• R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from
• halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
• R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
• the peptide is defined by Formula B:
• R 1 and R 2 are each independently selected from
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; and n is 4.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; R 8 and R 12 are methyl; R 10 is hydroxyl; and n is 4.
• the aromatic-cationic peptides of the present technology have a core structural motif of alternating aromatic and cationic amino acids.
• the peptide may be a tetrapeptide defined by any of Formulas C to F set forth below:
• amino acids of the aromatic-cationic peptides of the present technology can be any amino acid.
• amino acid is used to refer to any organic molecule that contains at least one amino group and at least one carboxyl group. In some embodiments, at least one amino group is at the a position relative to the carboxyl group.
• amino acids include, for example, amino acids that are synthesized in metabolic processes not associated with protein synthesis.
• amino acids ornithine and citrulline are synthesized in mammalian metabolism during the production of urea.
• the peptides useful in the present technology can contain one or more non-naturally occurring amino acids.
• the non-naturally occurring amino acids may be (L-), dextrorotatory (D-), or mixtures thereof.
• the peptide has no amino acids that are naturally occurring.
• Non-naturally occurring amino acids are those amino acids that typically are not synthesized in normal metabolic processes in living organisms, and do not naturally occur in proteins.
• the non-naturally occurring amino acids useful in the present technology are also not recognized by common proteases.
• the non-naturally occurring amino acid can be present at any position in the peptide.
• the non-naturally occurring amino acid can be at the N terminus, the C-terminus, or at any position between the N-terminus and the C-terminus.
• the non-natural amino acids may, for example, comprise alkyl, aryl, or alkylaryl groups.
• alkyl amino acids include a-aminobutyric acid, ⁇ -aminobutyric acid, ⁇ -aminobutyric acid, ⁇ -aminovaleric acid, and ⁇ -aminocaproic acid.
• aryl amino acids include ortho-, meta, and para-aminobenzoic acid.
• alkylaryl amino acids include ortho-, meta-, and para-aminophenyl acetic acid, and ⁇ -phenyl- ⁇ -aminobutyric acid.
• Non-naturally occurring amino acids also include derivatives of naturally occurring amino acids.
• the derivatives of naturally occurring amino acids may, for example, include the addition of one or more chemical groups to the naturally occurring amino acid.
• one or more chemical groups can be added to one or more of the 2', 3', 4', 5', or 6' position of the aromatic ring of a phenylalanine or tyrosine residue, or the 4', 5', 6', or 7' position of the benzo ring of a tryptophan residue.
• the group can be any chemical group that can be added to an aromatic ring.
• Some examples of such groups include branched or unbranched C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, or t-butyl, C 1 -C 4 alkyloxy (i.e., alkoxy), amino, C 1 -C 4 alkylamino and C 1 -C 4 dialkylamino (e.g., methylamino, dimethylamino), nitro, hydroxyl, halo (i.e., fluoro, chloro, bromo, or iodo).
• Some specific examples of non-naturally occurring derivatives of naturally occurring amino acids include norvaline (Nva), norleucine (Nle), and hydroxyproline (Hyp).
• Another example of a modification of an amino acid in a peptide useful in the present methods is the derivatization of a carboxyl group of an aspartic acid or a glutamic acid residue of the peptide.
• derivatization is amidation with ammonia or with a primary or secondary amine, e.g., methylamine, ethylamine, dimethylamine or diethylamine.
• Another example of derivatization includes esterification with, for example, methyl or ethyl alcohol.
• Another such modification includes derivatization of an amino group of a lysine, arginine, or histidine residue.
• amino groups can be acylated.
• suitable acyl groups include, for example, a benzoyl group or an alkanoyl group comprising any of the C 1 -C4 alkyl groups mentioned above, such as an acetyl or propionyl group.
• the non-naturally occurring amino acids are resistant, and in some embodiments insensitive, to common proteases.
• non-naturally occurring amino acids that are resistant or insensitive to proteases include the dextrorotatory (D-) form of any of the above-mentioned naturally occurring L-amino acids, as well as L- and/or D non- naturally occurring amino acids.
• D-amino acids do not normally occur in proteins, although they are found in certain peptide antibiotics that are synthesized by means other than the normal ribosomal protein synthetic machinery of the cell, as used herein, the D-amino acids are considered to be non-naturally occurring amino acids.
• the peptides useful in the methods of the present technology should have less than five, less than four, less than three, or less than two contiguous L-amino acids recognized by common proteases, irrespective of whether the amino acids are naturally or non-naturally occurring.
• the peptide has only D-amino acids, and no L-amino acids.
• the peptide contains protease sensitive sequences of amino acids, at least one of the amino acids is a non-naturally-occurring D-amino acid, thereby conferring protease resistance.
• An example of a protease sensitive sequence includes two or more contiguous basic amino acids that are readily cleaved by common proteases, such as endopeptidases and trypsin. Examples of basic amino acids include arginine, lysine and histidine.
• the aromatic-cationic peptides have a minimum number of net positive charges at physiological pH in comparison to the total number of amino acid residues in the peptide.
• the minimum number of net positive charges at physiological pH is referred to below as (p m ).
• the total number of amino acid residues in the peptide is referred to below as (r).
• physiological pH refers to the normal pH in the cells of the tissues and organs of the mammalian body.
• physiological pH refers to the normal pH in the cells of the tissues and organs of the mammalian body.
• physiological pH of a human is normally approximately 7.4, but normal physiological pH in mammals may be any pH from about 7.0 to about 7.8.
• a peptide typically has a positively charged N-terminal amino group and a negatively charged C-terminal carboxyl group. The charges cancel each other out at physiological pH.
• the peptide Tyr-Arg-Phe-Lys- Glu-His-Trp-Arg has one negatively charged amino acid (i.e., Glu) and four positively charged amino acids (i.e., two Arg residues, one Lys, and one His). Therefore, the above peptide has a net positive charge of three.
• the aromatic-cationic peptides have a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 2p m is the largest number that is less than or equal to r + 1.
• the relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) is as follows:
• the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) are equal.
• the peptides have three or four amino acid residues and a minimum of one net positive charge, or a minimum of two net positive charges, or a minimum of three net positive charges.
• the aromatic-cationic peptides should also have a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges at physiological pH (p t ) wherein 3 a is the largest number that is less than or equal to p t + 1, except that when p t is 1 , a may also be 1.
• the relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) is as follows:
• the aromatic-cationic peptides have a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) wherein 2a is the largest number that is less than or equal to p t + 1.
• the relationship between the minimum number of aromatic amino acid residues (a) and the total number of net positive charges (p t ) is as follows:
• the number of aromatic groups (a) and the total number of net positive charges (pt) are equal.
• carboxyl groups are amidated with, for example, ammonia to form the C-terminal amide.
• the terminal carboxyl group of the C-terminal amino acid may be amidated with any primary or secondary amine.
• the primary or secondary amine may, for example, be an alkyl, especially a branched or unbranched C 1 -C 4 alkyl, or an aryl amine.
• amino acid at the C-terminus of the peptide may be converted to an amido, N-methylamido, N-ethylamido, N,N-dimethylamido, ⁇ , ⁇ -diethyl amido, N-methyl-N- ethylamido, N-phenylamido or N-phenyl-N-ethylamido group.
• the free carboxylate groups of the asparagine, glutamine, aspartic acid, and glutamic acid residues not occurring at the C-terminus of the aromatic-cationic peptides of the present technology may also be amidated wherever they occur within the peptide.
• the amidation at these internal positions may be with ammonia or any of the primary or secondary amines described herein.
• the aromatic-cationic peptide useful in the methods of the present technology is a tripeptide having two net positive charges and at least one aromatic amino acid.
• the aromatic-cationic peptide useful in the methods of the present technology is a tripeptide having two net positive charges and two aromatic amino acids.
• Aromatic-cationic peptides useful in the methods of the present technology include, but are not limited to, the following peptide examples:
• the aromatic-cationic peptide is a peptide having:
• 2p m is the largest number that is less than or equal to r+1, and a may be equal to p t .
• the aromatic-cationic peptide may be a water-soluble peptide having a minimum of two or a minimum of three positive charges.
• a peptide has the formula Tyr-D-Arg-Phe-Lys-NH 2 .
• Tyr-D- Arg-Phe-Lys-NH 2 has a net positive charge of three, contributed by the amino acids tyrosine, arginine, and lysine and has two aromatic groups contributed by the amino acids
• the aromatic-cationic peptide does not have a tyrosine residue or a derivative of tyrosine at the N-terminus (i.e., amino acid position 1).
• the amino acid at the N-terminus can be any naturally-occurring or non-naturally-occurring amino acid other than tyrosine.
• the amino acid at the N-terminus is phenylalanine or its derivative.
• Exemplary derivatives of phenylalanine include 2'- methylphenylalanine (Mmp), 2',6'-dimethylphenylalanine (2',6'-Dmp), N,2',6'- trimethylphenylalanine (Tmp), and 2'-hydroxy-6'-methylphenylalanine (Hmp).
• an aromatic-cationic peptide that does not have a tyrosine residue or a derivative of tyrosine at the N-terminus is a peptide with the formula Phe-D-Arg-Phe-Lys- NH 2 .
• the N-terminal phenylalanine can be a derivative of phenylalanine such as 2',6'-dimethylphenylalanine (2'6'-Dmp).
• the amino acid sequence of 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 is rearranged such that Dmt is not at the N-terminus.
• An example of such an aromatic-cationic peptide is a peptide having the formula of D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
• Suitable substitution variants of the peptides listed herein include conservative amino acid substitutions.
• Amino acids may be grouped according to their physicochemical characteristics as follows: (a) Non-polar amino acids: Ala(A) Ser(S) Thr(T) Pro(P) Gly(G) Cys (C);
• Aromatic amino acids Phe(F) Tyr(Y) Trp(W) His (H).
• substitutions of an amino acid in a peptide by another amino acid in the same group are referred to as a conservative substitution and may preserve the physicochemical characteristics of the original peptide.
• substitutions of an amino acid in a peptide by another amino acid in a different group are generally more likely to alter the
• Examples of peptides that have a tyrosine residue or a tyrosine derivative at the N- terminus include, but are not limited to, the aromatic-cationic peptides shown in Table 6.
• Examples of peptides that do not have a tyrosine residue or a tyrosine derivative at the N-terminus include, but are not limited to, the aromatic-cationic peptides shown in Table 7.
• amino acids of the peptides shown in Table 6 and 7 may be in either the L- or the D- configuration.
• ameliorating or preventing a medical disease or condition in a subject in need thereof comprising administering a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to an acrylamido compound, Ac* compound, phenyl-substituted maleimide compound, or PSMc* compound to the subject thereby treating, ameliorating, or preventing the medical disease or condition.
• one or more peptide conjugate(s) may be: (1) co-formulated and administered or delivered alone or simultaneously in a combined formulation with other acrylamido compounds, Ac* compounds, phenyl-substituted maleimide compounds, PSMc* compounds, or aromatic-cationic peptides; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
• the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
• an effective dosage of each active ingredient is administered sequentially, i.e., serially
• effective dosages of two or more active ingredients are administered together.
• Various sequences of intermittent combination therapy may also be used.
• Administering combinations of aromatic peptides and acrylamido compounds, Ac* compounds, phenyl-substituted maleimide compounds, or PSMc* compounds can result in a synergistic biological effect when administered in a therapeutically effective amount to a subject suffering from a medical disease or condition and in need of treatment.
• An advantage of such an approach is that lower doses of aromatic-cationic peptide and/or acrylamido compound, Ac* compound, phenyl-substituted maleimide compound, or PSMc* compound may be needed to prevent, ameliorate, or treat a medical disease or condition in a subject.
• the combination therapy comprises administering to a subject in need thereof an aromatic-cationic peptide
• composition combined with one or more acrylamido compounds, Ac* compounds, phenyl- substituted maleimide compounds, or PSMc* compounds are chemically linked.
• the acrylamido compound, Ac* compound, phenyl-substituted maleimide compound, or PSMc* compound and the aromatic-cationic peptide are physically linked.
• the acrylamido compound, Ac* compound, phenyl-substituted maleimide compound, or PSMc* compound and the aromatic-cationic peptide are not linked.
• Ischemia in a tissue or organ of a mammal is a multifaceted pathological condition which is caused by oxygen deprivation (hypoxia) and/or glucose (e.g., substrate) deprivation.
• Oxygen and/or glucose deprivation in cells of a tissue or organ leads to a reduction or total loss of energy generating capacity and consequent loss of function of active ion transport across the cell membranes.
• Oxygen and/or glucose deprivation also leads to pathological changes in other cell membranes, including permeability transition in the mitochondrial membranes.
• other molecules, such as apoptotic proteins normally
• Ischemia or hypoxia in a particular tissue or organ may be caused by a loss or severe reduction in blood supply to the tissue or organ.
• the loss or severe reduction in blood supply may, for example, be due to thromboembolic stroke, coronary atherosclerosis, or peripheral vascular disease.
• the tissue affected by ischemia or hypoxia is typically muscle, such as cardiac, skeletal, or smooth muscle.
• the organ affected by ischemia or hypoxia may be any organ that is subject to ischemia or hypoxia.
• organs affected by ischemia or hypoxia include brain, heart, kidney, and prostate.
• cardiac muscle ischemia or hypoxia is commonly caused by atherosclerotic or thrombotic blockages which lead to the reduction or loss of oxygen delivery to the cardiac tissues by the cardiac arterial and capillary blood supply.
• Such cardiac ischemia or hypoxia may cause pain and necrosis of the affected cardiac muscle, and ultimately may lead to cardiac failure.
• Ischemia or hypoxia in skeletal muscle or smooth muscle may arise from similar causes.
• ischemia or hypoxia in intestinal smooth muscle or skeletal muscle of the limbs may also be caused by atherosclerotic or thrombotic blockages.
• Reperfusion is the restoration of blood flow to any organ or tissue in which the flow of blood is decreased or blocked.
• blood flow can be restored to any organ or tissue affected by ischemia or hypoxia.
• the restoration of blood flow can occur by any method known to those in the art. For instance, reperfusion of ischemic cardiac tissues may arise from angioplasty, coronary artery bypass graft, or the use of thrombolytic drugs.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing oxLDL-induced CD36 mRNA and protein levels, and foam cell formation in mouse peritoneal macrophages.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• peptide conjugates of the present technology are useful in reducing oxLDL-induced CD36 mRNA and protein levels, and foam cell formation in mouse peritoneal macrophages.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing infarct volume and hemispheric swelling in a subject suffering from acute cerebral ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology are useful in reducing infarct volume and hemispheric swelling in a subject suffering from acute cerebral ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing the decrease in reduced glutathione (GSH) in post- ischemic brain in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology are useful in reducing the decrease in reduced glutathione (GSH) in post-ischemic brain in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing CD36 expression in post-ischemic brain in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology are useful in reducing CD36 expression in post-ischemic brain in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing CD36 expression in renal tubular cells after unilateral ureteral obstruction (UUO) in a subject in need thereof.
• UUO unilateral ureteral obstruction
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing lipid peroxidation in a kidney after UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg- 2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing tubular cell apoptosis in an obstructed kidney after UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing macrophage infiltration in an obstructed kidney induced by UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g. , those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing interstitial fibrosis in an obstructed kidney after UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg- 2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing up-regulation of CD36 expression in cold storage of isolated hearts.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing lipid peroxidation in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• the peptide conjugates of the present technology are useful in reducing lipid peroxidation in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in abolishing endothelial apoptosis in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• the peptide conjugates of the present technology are useful in abolishing endothelial apoptosis in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preserving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• the peptide conjugates of the present technology are useful in preserving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing damage to renal proximal tubules in diabetic subjects.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg- 2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing renal tubular epithelial cell apoptosis in diabetic subjects.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in methods for reducing elevated CD36 expression associated with various diseases and conditions.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• diseases and conditions characterized by increased CD36 expression include, but are not limited to atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy and obesity.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in methods for reducing CD36 expression in subjects suffering from complications of diabetes.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• Complications of diabetes include, but are not limited to, nephropathy, neuropathy, retinopathy, coronary artery disease, and peripheral vascular disease.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in methods for reducing CD36 expression in removed organs and tissues.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• the method comprises contacting the removed organ or tissue with an effective amount of a composition described herein.
• An organ or tissue may, for example, be removed from a donor for autologous or heterologous transplantation.
• organs and tissues amenable to methods of the present technology include, but are not limited to, heart, lungs, pancreas, kidney, liver, skin, etc.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof will translocate to and accumulate within mitochondria.
• pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology will translocate to and accumulate within mitochondria.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in protecting against mitochondrial permeability transition (MPT) induced by Ca 2+ overload and 3-nitropropionic acid (3NP).
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in protecting against mitochondrial permeability transition (MPT) induced by Ca 2+ overload and 3-nitropropionic acid (3NP).
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg- 2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in protecting myocardial contractile force during ischemia- reperfusion in cardiac tissue.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• compositions of the present disclosure can also be used in the treatment or prophylaxis of neurodegenerative diseases associated with MPT.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preserving an organ of a mammal prior to transplantation.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg- 2'6'-Dmt-Lys-Phe-NH 2
• compositions of the present disclosure can be administered to a subject prior to organ removal, for example, and used to prevent MPT in the removed organ.
• the removed organ may be placed in a standard buffered solution, such as those commonly used in the art.
• a removed heart may be placed in a cardioplegic solution containing the compositions described herein.
• concentration of compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.1 nM to about 10 ⁇ .
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• a side effect of the drug includes MPT
• mammals taking such drugs would greatly benefit from administration of the compositions disclosed herein.
• An example of a drug which induces cell toxicity by effecting MPT is the chemotherapy drug Adriamycin.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in ameliorating, diminishing, or preventing the side effects of drugs such as adriamycin.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in ameliorating, diminishing or preventing the side effects of drugs such as adriamycin.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in dose-dependently scavenging H 2 O 2 .
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in dose-dependently scavenging H 2 O 2 .
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in dose-dependently inhibiting linoleic acid peroxidation induced by ABAP and reducing the rate of linoleic acid peroxidation induced by ABAP.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in dose-dependently inhibiting linoleic acid peroxidation induced by ABAP and reducing the rate of linoleic acid peroxidation induced by ABAP.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in inhibiting mitochondrial production of hydrogen peroxide, e.g., as measured by luminol
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing spontaneous generation of hydrogen peroxide by mitochondria in certain stress or disease states.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in inhibiting spontaneous production of hydrogen peroxide in mitochondria and hydrogen peroxide production, e.g., as stimulated by antimycin.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology are useful in inhibiting spontaneous production of hydrogen peroxide in mitochondria and hydrogen peroxide production, e.g., as stimulated by antimycin.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in decreasing intracellular ROS (reactive oxygen species) and increasing survival in cells of a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• peptide conjugates of the present technology are useful in decreasing intracellular ROS (reactive oxygen species) and increasing survival in cells of a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing loss of cell viability in subjects suffering from a disease or condition characterized by mitochondrial permeability transition.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in preventing loss of cell viability in subjects suffering from a disease or condition characterized by mitochondrial permeability transition.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in decreasing the percent of cells showing increased caspase activity in a subject in need thereof.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in decreasing the percent of cells showing increased caspase activity in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in decreasing the rate of ROS accumulation in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in decreasing the rate of ROS accumulation in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in inhibiting lipid peroxidation in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in inhibiting lipid peroxidation in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing mitochondrial depolarization and ROS accumulation in a subject in need thereof.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in preventing mitochondrial depolarization and ROS accumulation in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing apoptosis in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in preventing apoptosis in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in improving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• the peptide conjugates of the present technology are useful in improving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing apoptosis in endothelial cells and myocytes in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology are useful in preventing apoptosis in endothelial cells and myocytes in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in improving survival of pancreatic cells in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology are useful in improving survival of pancreatic cells in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing apoptosis and increasing viability in islet cells of pancreas in subjects in need thereof.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing oxidative damage in pancreatic islet cells in subjects in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in protecting dopaminergic cells against MPP+ toxicity in subjects in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g. , those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing loss of dopaminergic neurons in subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in increasing striatal dopamine, DOPAC (3,4- dihydroxyphenylacetic acid) and HVA (homo vanillic acid) levels in subjects in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g., those including D-Arg- 2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• mammals in need of reducing oxidative damage are those mammals suffering from a disease, condition or treatment associated with oxidative damage.
• a mammal in need thereof may be a mammal undergoing a treatment associated with oxidative damage.
• the mammal may be undergoing reperfusion.
• “Reperfusion” refers to the restoration of blood flow to any organ or tissue in which the flow of blood is decreased or blocked. The restoration of blood flow during reperfusion leads to respiratory burst and formation of free radicals.
• a mammal in need thereof is a mammal suffering from a disease or condition associated with oxidative damage.
• the oxidative damage can occur in any cell, tissue or organ of the mammal.
• cells, tissues or organs affected by oxidative damage include, but are not limited to, endothelial cells, epithelial cells, nervous system cells, skin, heart, lung, kidney, eye and liver.
• lipid peroxidation and an inflammatory process are associated with oxidative damage for a disease or condition.
• Lipid peroxidation refers to oxidative modification of lipids.
• the lipids can be present in the membrane of a cell. This modification of membrane lipids typically results in change and/or damage to the membrane function of a cell.
• lipid peroxidation can also occur in lipids or lipoproteins exogenous to a cell. For example, low-density
• Intravirus process refers to the activation of the immune system.
• the immune system is activated by an antigenic substance.
• the antigenic substance can be any substance recognized by the immune system, and include self-derived and foreign- derived substances.
• diseases or conditions resulting from an inflammatory response to self-derived substances include arthritis and multiple sclerosis.
• foreign substances include viruses and bacteria.
• the bacteria can be any bacteria, and include gram-negative and gram-positive bacteria.
• Gram-negative bacteria contain lipopolysaccharide in the bacteria wall. Examples of gram-negative bacteria include Escherichia coli, Klebsiella pneumoniae, Proteus species, Pseudomonas aeruginosa, Serratia, and Bacteroides. Examples of gram-positive bacteria include pneumococci and streptococci.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or the peptide conjugates of the present technology (e.g., those including D- Arg-2'6'-Dmt-Lys-Phe-NH 2 ) are useful in reducing oxidative damage associated with a neurodegenerative disease or condition.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the neurodegenerative disease can affect any cell, tissue or organ of the central and peripheral nervous system.
• Non-limiting examples of such cells, tissues, and organs include the brain, spinal cord, neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia.
• the neurodegenerative condition can be an acute condition, such as a stroke or a traumatic brain or spinal cord injury.
• the neurodegenerative disease or condition is a chronic neurodegenerative condition.
• the free radicals can, for example, cause damage to a protein.
• An example of such a protein is amyloid precursor protein.
• Non-limiting examples of chronic neurodegenerative diseases associated with damage by free radicals include Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS).
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in treating preeclampsia, diabetes, and symptoms of and conditions associated with aging, such as macular degeneration, and wrinkles.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in treating preeclampsia, diabetes, and symptoms of and conditions associated with aging, such as macular degeneration, and wrinkles.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in reducing oxidative damage in an organ of a mammal prior to transplantation.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• compositions of the present technology can be used to reduce oxidative damage from reperfusion of the transplanted organ.
• the organ can be any organ suitable for transplantation.
• the organ is a removed organ.
• examples of such organs include the heart, liver, kidney, lung, and pancreatic islets.
• the removed organ is placed in a suitable medium, such as in a standard buffered solution commonly used in the art.
• the concentration of disclosed compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.01 nM to about 10 ⁇ , about 0.1 nM to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , or about 1 nM to about 100 nM.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in reducing oxidative damage in a cell in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Cells in need of reducing oxidative damage are generally those cells in which the cell membrane or DNA has been damaged by free radicals, for example, ROS and/or RNS.
• Examples of cells capable of sustaining oxidative damage include, but are not limited to, pancreatic islet cells, myocytes, endothelial cells, neuronal cells, stem cells, and other cell types discussed herein.
• the cells can be tissue culture cells. Alternatively, the cells may be obtained from a mammal. In one instance, the cells can be damaged by oxidative damage as a result of a cellular insult.
• Cellular insults include, for example, a disease or condition (e.g., diabetes, etc.) or ultraviolet radiation (e.g., sun, etc.).
• pancreatic islet cells damaged by oxidative damage as a result of diabetes can be obtained from a mammal.
• the treated cells may be capable of regenerating.
• Such regenerated cells may be re-introduced into the mammal from which they were derived as a therapeutic treatment for a disease or condition.
• a disease or condition is diabetes.
• Oxidative damage is considered to be “reduced” if the amount of oxidative damage in a mammal, a removed organ, or a cell is decreased after administration of an effective amount of the compositions described herein. Typically, oxidative damage is considered to be reduced if the oxidative damage is decreased by at least about 1%, 5%, 10%, at least about 25%, at least about 50%>, at least about 75%, or at least about 90%.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in regulating oxidation state of muscle tissue.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology are useful in regulating oxidation state of muscle tissue.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in regulating oxidation state of muscle tissue in lean and obese human subjects.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology e.g. , those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in regulating insulin resistance in muscle tissue.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the peptide conjugates of the present technology are useful in regulating insulin resistance in muscle tissue.
• insulin resistance induced by obesity or a high-fat diet affects mitochondrial bioenergetics.
• mitochondrial bioenergetics it is thought that the oversupply of metabolic substrates causes a reduction on the function of the mitochondrial respiratory system, and an increase in ROS production and shift in the overall redox environment to a more oxidized state. If persistent, this leads to development of insulin resistance.
• Linking mitochondrial bioenergetics to the etiology of insulin resistance has a number of clinical implications.
• insulin resistance (NIDDM) in humans often results in weight gain and, in selected individuals, increased variability of blood sugar with resulting metabolic and clinical consequences.
• NIDDM insulin resistance
• the examples shown herein demonstrate that treatment of mitochondrial defects with the compositions disclosed herein provides a new and surprising approach to treating or preventing insulin resistance without the metabolic side-effects of increased insulin.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing insulin resistance.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• peptide conjugates of the present technology are useful in reducing insulin resistance.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful for prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder, or a subject having a disorder associated with insulin resistance.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• insulin resistance is generally associated with type II diabetes, coronary artery disease, renal dysfunction, atherosclerosis, obesity, hyperlipidemia, and essential hypertension. Insulin resistance is also associated with fatty liver, which can progress to chronic inflammation (NASH; "nonalcoholic
• insulin resistance syndromes including, but not limited to diabetes, underlie many of the major causes of morbidity and death of people over age 40.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in methods for the prevention and/or treatment of insulin resistance and associated syndromes in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• peptide conjugates of the present technology are useful in methods for the prevention and/or treatment of insulin resistance and associated syndromes in a subject in need thereof.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in improving the sensitivity of mammalian skeletal muscle tissues to insulin.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing drug-induced obesity, insulin resistance, and/or diabetes, wherein the compound is administered with a drug that shows the side-effect of causing one or more of these conditions (e.g., olanzapine, ZYPREXA®).
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in preventing drug- induced obesity, insulin resistance, and/or diabetes, wherein the compound is administered with a drug that shows the side-effect of causing one or more of these conditions (e.g. , olanzapine, ZYPREXA®).
• Increased or decreased insulin resistance or sensitivity can be readily detected by quantifying body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 O 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
• OGTT oral glucose tolerance
• markers of insulin signaling e.g., Akt-P, IRS-P
• mitochondrial function e.g., respiration or H 2 O 2 production
• markers of intracellular oxidative stress e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity
• mitochondrial enzyme activity e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in methods for preventing, in a subject, a disease or condition associated with insulin resistance in skeletal muscle tissues via modulating one or more signs or markers of insulin resistance, e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 O 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
• signs or markers of insulin resistance e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P,
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in methods for preventing, in a subject, a disease or condition associated with insulin resistance in skeletal muscle tissues via modulating one or more signs or markers of insulin resistance, e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 O 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
• signs or markers of insulin resistance e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 O 2 production), markers of intracellular oxidative
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in treating subjects at risk for a disease that is caused or contributed to by aberrant mitochondrial function or insulin resistance.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in treating subjects at risk for a disease that is caused or contributed to by aberrant mitochondrial function or insulin resistance.
• a prophylactic acrylamido compounds phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*), alone or in combination with one or more active agents (e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology can occur prior to the manifestation of symptoms characteristic of the aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression.
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology can occur prior to the manifestation of symptoms characteristic of the aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression.
• compositions of the present technology will act to enhance or improve mitochondrial function, and can be used for treating the subject.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in methods of modulating insulin resistance or sensitivity in a subject for therapeutic purposes.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in improving the histopathological score resulting from ischemia and reperfusion.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in improving the histopathological score resulting from ischemia and reperfusion.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in increasing the rate of ATP production after reperfusion in renal tissue following ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in increasing the rate of ATP production after reperfusion in renal tissue following ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in improving renal mitochondrial respiration following ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in improving renal mitochondrial respiration following ischemia.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in decreasing medullary fibrosis in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in decreasing interstitial fibrosis in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in decreasing interstitial fibrosis in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in decreasing tubular apoptosis in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in decreasing tubular apoptosis in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in decreasing macrophage infiltration in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in decreasing macrophage infiltration in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in increasing tubular proliferation in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in increasing tubular proliferation in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in decreasing oxidative damage in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• peptide conjugates of the present technology are useful in decreasing oxidative damage in UUO.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing renal dysfunction caused by a radiocontrast dye.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in reducing renal dysfunction caused by a radiocontrast dye.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in protecting renal tubules from radiocontrast dye injury.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in protecting renal tubules from radiocontrast dye injury.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in preventing renal tubular apoptosis induced by radiocontrast dye injury.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are useful in preventing renal tubular apoptosis induced by radiocontrast dye injury.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in protecting a subject's kidney from renal injury.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• ARI Acute renal injury
• GFR glomerular filtration rate
• the causes of ARI may be caused by various factors, falling into three categories: (1) pre -renal ARI, in which the kidneys fail to receive adequate blood supply, e.g., due to reduced systemic blood pressure as in shock/cardiac arrest, or subsequent to hemorrhage; (2) intrinsic ARI, in which the failure occurs within the kidney, e.g., due to drug-induced toxicity; and (3) post-renal ARI, caused by impairment of urine flow out of the kidney, as in ureteral obstruction due to kidney stones or bladder/prostate cancer. ARI may be associated with any one or a combination of these categories.
• Ischemia is a major cause of ARI. Ischemia of one or both kidneys is a common problem experienced during aortic surgery, renal transplantation, or during cardiovascular anesthesia. Surgical procedures involving clamping of the aorta and/or renal arteries, e.g., surgery for supra- and juxta-renal abdominal aortic aneurysms and renal transplantation, are also particularly liable to produce renal ischemia, leading to significant postoperative complications and early allograft rejection. In high-risk patients undergoing these surgeries, the incidence of renal dysfunction has been reported to be as high as 50%. The skilled artisan will understand that the above described causes of ischemia are not limited to the kidney, but may occur in other organs during surgical procedures.
• Subjects may also become vulnerable to ARI after receiving anesthesia, surgery, or a-adrenergic agonists because of related systemic or renal vasoconstriction. Additionally, systemic vasodilation caused by anaphylaxis, and anti-hypertensive drugs, sepsis or drug overdose may also cause ARI because the body's natural defense is to shut down, i.e., vasoconstriction of non-essential organs such as the kidneys.
• a subject at risk for ARI may be a subject undergoing an interruption or reduction of blood supply or blood pressure to the kidney.
• these subjects may be administered acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology prior to or simultaneously with such interruption or reduction of blood supply.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology may be administered after the therapeutic agent to treat ischemia.
• Nephrotoxins can cause direct toxicity on tubular epithelial cells.
• Nephrotoxins include, but are not limited to, therapeutic drugs, e.g., cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, radiocontrast dye (described in further detail below), pesticides (e.g., paraquat), and environmental contaminants (e.g., trichloroethylene and dichloroacetylene).
• therapeutic drugs e.g., cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, radiocontrast dye (described in further detail below), pesticides (e.g., paraquat), and environmental contaminants (e.g., trichloroethylene and dichloroacetylene).
• PAN puromycin aminonucleoside
• aminoglycosides such as gentamicin
• cephalosporins such as cephaloridine
• calcineurin inhibitors such as tacrolimus or sirolimus.
• Drug-induced nephrotoxicity may also be caused by non-steroidal anti-inflammatories, anti- retrovirals, anticytokines, immunosuppressants, oncological drugs, or angiotensin-converting- enzyme (ACE) inhibitors.
• ACE angiotensin-converting- enzyme
• the drug-induced nephrotoxicity may further be caused by analgesic abuse, ciprofloxacin, clopidogrel, cocaine, cox-2 inhibitors, diuretics, foscamet, gold, ifosfamide, immunoglobulin, Chinese herbs, interferon, lithium, mannitol, mesalamine, mitomycin, nitrosoureas, penicillamine, penicillins, pentamidine, quinine, rifampin, streptozocin, sulfonamides, ticlopidine, triamterene, valproic acid, doxorubicin, glycerol, cidofovir, tobramycin, neomycin sulfate, colistimethate, vancomycin, amikacin, cefotaxime, cisplatin, acyclovir, lithium, interleukin-2, cyclosporin, or indinavir.
• analgesic abuse ciprofloxaci
• nephrotoxins In addition to direct toxicity on tubular epithelial cells, some nephrotoxins also reduce renal perfusion, causing injury to zones known to have limited oxygen availability (inner medullary region). Such nephrotoxins include amphotericin and radiocontrast dyes. Renal failure can result even from clinically relevant doses of these drugs when combined with ischemia, volume depletion, obstruction, or infection. An example is the use of radiocontrast dye in patients with impaired renal function. The incidence of contrast dye- induced nephropathy (CIN) is 3-8% in the normal patient, but increases to 25% for patients with diabetes mellitus. Most cases of ARI occur in patients with predisposing co-morbidities (McCombs, P.R. & Roberts, B., Surg Gynecol. Obstet, 148: 175-178 (1979)).
• CIN contrast dye- induced nephropathy
• a subject at risk for ARI is receiving one or more therapeutic drugs that have a nephrotoxic effect.
• the subject is administered acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt- Lys-Phe-NH 2 ), or peptide conjugates of the present technology prior to or simultaneously with such therapeutic agents.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt- Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology may be administered after the therapeutic agent to treat
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• CIN is an important cause of acute renal failure.
• CIN is defined as acute renal failure occurring within 48 hours of exposure to intravascular radiographic contrast material, and remains a common complication of radiographic procedures.
• CIN arises when a subject is exposed to radiocontrast dye, such as during coronary, cardiac, or neuro-angiography procedures. Contrast dye is essential for many diagnostic and interventional procedures because it enables doctors to visualize blocked body tissues.
• a creatinine test can be used to monitor the onset of CIN, treatment of the condition, and efficacy of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology in treating or preventing CIN.
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are administered to a subject prior to or simultaneously with the administration of a contrast agent in order to provide protection against CIN.
• the subject may receive the compositions from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, or about 1 to 48 hours prior to receiving the contrast agent.
• the subject may be administered the compositions at about the same time as the contrast agent.
• administration of the compositions to the subject may continue following administration of the contrast agent.
• the subject continues to receive the compositions at intervals of about 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, and 48 hours following administration of the contrast agent, in order to provide a protective or prophylactic effect against CIN.
• the subject receives the compositions from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, about 1 to 48 hours, or about 1 to 72 hours after receiving the contrast agent.
• the subject may exhibit one or more signs or symptoms of CIN prior to receiving the compositions of the present technology, such as increased serum creatinine levels and/or decreased urine volume.
• Administration of the compositions of the present technology improves one or more of these indicators of kidney function in the subject compared to a control subject not administered the compositions.
• a subject in need thereof may be a subject having impairment of urine flow. Obstruction of the flow of urine can occur anywhere in the urinary tract and has many possible causes, including but not limited to, kidney stones or
• UUO is a common clinical disorder associated with obstructed urine flow. It is also associated with tubular cell apoptosis, macrophage infiltration, and interstitial fibrosis. Interstitial fibrosis leads to a hypoxic environment and contributes to progressive decline in renal function despite surgical correction.
• a subject having or at risk for UUO may be administered acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to prevent or treat ARI.
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• a method for protecting a kidney from renal fibrosis in a mammal in need thereof comprises administering to the mammal an effective amount of acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology as described herein.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the compositions described herein can be administered to a mammal in need thereof, as described herein, by any method known to those skilled in the art.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in methods for treating ARI in a mammal in need thereof.
• the method comprises administering to the mammal an effective amount of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology as described herein.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the compositions described herein can be administered to a mammal in need thereof, as described herein, by any method known to those skilled in the art.
• the methods of the present technology may be particularly useful in patients with renal insufficiency, renal failure, or end-stage renal disease attributable at least in part to a nephrotoxicity of a drug or chemical.
• Other indications may include creatinine clearance levels of lower than 97 (men) and 88 (women) mL/min, or a blood urea level of 20-25 mg/dl or higher.
• the treatment may be useful in patients with microalbuminuria, macroalbuminuria, and/or proteinuria levels of over 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g or more per a 24 hour period, and/or serum creatinine levels of about 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4.0, 4.5, 5, 5.5, 6, 7, 8, 9, 10 mg/dl or higher.
• the methods of the present technology can be used to slow or reverse the progression of renal disease in patients whose renal function is below normal, relative to control subjects.
• the methods of the present technology slow the loss of renal function.
• loss of renal function is slowed by at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%), 90%), 100%) or more, relative to control subjects.
• the methods of the present technology improve the patient's serum creatinine levels, proteinuria, and/or urinary albumin excretion.
• the patient's serum creatinine levels, proteinuria, and/or urinary albumin excretion is improved by at least 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or more, relative to control subjects.
• Non-limiting illustrative methods for assessing renal function are described herein and, for example, in WO 01/66140.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in protecting a subject's kidney from ARI prior to transplantation.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• a removed kidney can be placed in a solution containing the compositions described herein.
• concentration of compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.01 nM to about 10 ⁇ , about 0.1 nM to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , or about 1 nM to about 100 nM.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in preventing or treating ARI and are also applicable to tissue injury and organ failure in other systems besides the kidney.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in minimizing cell death, inflammation, and fibrosis.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in methods of treating a subject having a tissue injury, e.g., noninfectious pathological conditions such as pancreatitis, ischemia, multiple trauma, hemorrhagic shock, and immune -mediated organ injury.
• tissue injury e.g., noninfectious pathological conditions such as pancreatitis, ischemia, multiple trauma, hemorrhagic shock, and immune -mediated organ injury.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the tissue injury can be associated with, for example, aortic aneurysm repair, multiple trauma, peripheral vascular disease, renal vascular disease, myocardial infarction, stroke, sepsis, and multi-organ failure.
• the present technology relates to a method of treating a subject having a tissue such as from heart, brain, vasculature, gut, liver, kidney and eye that is subject to an injury and/or ischemic event.
• the method includes administering to the subject a therapeutically effective amount of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to provide a therapeutic or prophylactic effect.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology to provide a therapeutic or prophylactic
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in improving a function of one or more organs selected from the group consisting of: renal, lung, heart, liver, brain, pancreas, and the like.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in the prevention and/or treatment of acute hepatic injury caused by ischemia, drugs (e.g., acetaminophen, alcohol), viruses, obesity (e.g., non-alcoholic steatohepatitis), and obstruction (e.g., bile duct obstruction, tumors).
• drugs e.g., acetaminophen, alcohol
• viruses e.g., obesity
• obesity e.g., non-alcoholic steatohepatitis
• obstruction e.g., bile duct obstruction, tumors.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in preventing or treating acute liver failure (ALF) in a subject.
• ALF acute liver failure
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• ALF is a clinical condition that results from severe and extensive damage of liver cells leading to failure of the liver to function normally.
• ALF results from massive necrosis of liver cells leading to hepatic encephalopathy and severe impairment of hepatic function.
• ALF viral hepatitis
• drug toxicity drug toxicity
• frequent alcohol intoxication frequent alcohol intoxication
• autoimmune hepatitis hepatitis
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• a drug or agent known or suspected to induced hepatotoxicity e.g. , acetaminophen
• the subject may receive the compositions from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, or about 1 to 48 hours prior to receiving the drug or agent.
• the subject may be administered the compositions at about the same time as the drug or agent to provide a prophylactic effect against ALF caused by the drug or agent.
• administration of the compositions to the subject may continue following administration of the drug or agent.
• the subject may continue to receive the compositions at intervals of about 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, and 48 hours following administration of the drug or agent, in order to provide a protective or prophylactic effect.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are administered to a subject exhibiting one or more signs or symptoms of ALF, including, but not limited to, elevated levels of hepatic enzymes (transaminases, alkaline phosphatase), elevated serum bilirubin, ammonia, glucose, lactate, or creatinine.
• compositions of the present technology improves one or more of these indicators of liver function in the subject compared to a control subject not administered the compositions.
• the subject may receive acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, about 1 to 48 hours, or about 1 to 72 hours after the first signs or symptoms of ALF.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology from about 1 to 2 hours
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or ameliorating the local and distant pathophysiological effects of burn injury, including, but not limited to, hypermetabolism and organ damage.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing burn injuries and systemic conditions associated with a burn injury.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are administered to a subject following a burn and after the onset of detectable symptoms of systemic injury.
• treatment is used herein in its broadest sense and refers to use of a composition for a partial or complete cure of the burn and/or secondary
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are administered to a subject following a burn, but before the onset of detectable symptoms of systemic injury in order to protect against or provide prophylaxis for the systemic injury, such as organ damage or hypermetabolism.
• prevention is used herein in its broadest sense and refers to a prophylactic use which completely or partially prevents local injury to the skin or systemic injury, such as organ dysfunction or hypermetabolism following burns. It is also contemplated that the compositions may be administered to a subject at risk of receiving burns.
• Burns are generally classified according to their severity and extent. First degree burns are the mildest and typically affect only the epidermis. The burn site appears red, and is painful, dry, devoid of blisters, and may be slightly moist due to fluid leakage. Mild sunburn is typical of a first degree burn. In second degree burns, both the epidermis and dermis are affected. Blisters usually appear on the skin, with damage to nerves and sebaceous glands. Third degree burns are the most serious, with damage to all layers of the skin, including subcutaneous tissue. Typically there are no blisters, with the burned surface appearing white or black due to charring, or bright red due to blood in the bottom of the wound. In most cases, the burn penetrates the superficial fascia, extending into the muscle layers where arteries and veins are affected. Because of nerve damage, it is possible for the burn to be painless.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in the treatment of burns from any cause, including dry heat or cold burns, scalds, sunburn, electrical burns, chemical agents such as acids and alkalis, including hydrofluoric acid, formic acid, anhydrous ammonia, cement, and phenol, or radiation burns.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• Burns resulting from exposure to either high or low temperature are within the scope of the present technology. The severity and extent of the burn may vary, but secondary organ damage or hypermetabolism will usually arise when the burns are very extensive or very severe (second or third degree burns). The development of secondary organ dysfunction or failure is dependent on the extent of the burn, the response of the patient's immune system and other factors, such as infection and sepsis.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• Myocardial contractility also may be reduced by the release of TNF- ⁇ .
• Activated neutrophils are sequestered in dermal and distant organs, such as the lung, within hours following a burn injury, resulting in the release of toxic reactive oxygen species and proteases and producing vascular endothelial cell damage.
• plasma and blood leak into the interstitial and intra-alveolar spaces, resulting in pulmonary edema.
• a decrease in pulmonary function can occur in severely burned patients, as a result of bronchoconstriction caused by humoral factors, such as histamine, serotonin, and thromboxane A2.
• Burn-induced mitochondrial skeletal muscle dysfunction is thought to result from defects in oxidative phosphorylation (OXPHOS) via stimulation of mitochondrial production of reactive oxygen species (ROS) and the resulting damage to the mitochondrial DNA (mtDNA).
• OXPHOS oxidative phosphorylation
• ROS reactive oxygen species
• mtDNA mitochondrial DNA
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in inducing ATP synthesis via a recovery of the
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating a wound resulting from a burn injury.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology may be administered systemically or topically to the wound.
• Burn wounds are typically uneven in depth and severity. There are typically significant areas around the coagulated tissue where injury may be reversible and damage mediated by the inflammatory and immune cells to the microvasculature of the skin could be prevented.
• acrylamido compounds e.g., phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in
• Wound contraction is the process which diminishes the size of a full-thickness open wound, especially a full-thickness burn.
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology slows or ameliorates the effects of wound contraction.
• Wound contraction is the process which diminishes the size of a full-thickness open wound, especially a full-thickness burn.
• the tensions developed during contracture and the formation of subcutaneous fibrous tissue can result in deformity, and in particular to fixed flexure or fixed extension of a joint where the wound involves an area over the joint. Such complications are especially relevant in burn healing. No wound contraction will occur when there is no injury to the tissue, and maximum contraction will occur when the burn is full thickness and no viable tissue remains in the wound.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in preventing progression of a burn injury from a second degree burn to a third degree burn.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in decreasing scarring or the formation of scar tissue attendant the healing process at a burn site.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• Scarring is the formation of fibrous tissue at sites where normal tissue has been destroyed.
• the present disclosure thus also includes a method for decreasing scarring following a second or third degree burn.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing damage to distant organs or tissues in a subject suffering from a burn.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• systemic inflammatory responses arise in subjects following burn injury, and that it is this generalized inflammation which leads to remote tissue injury which is expressed as the dysfunction and failure of organs remote from the injury site.
• Systemic injury including organ dysfunction and hypermetabolism, is typically associated with second and third degree burns.
• a characteristic of the systemic injury, i.e., organ dysfunction or hypermetabolism, is that the burn which provokes the subsequent injury or condition does not directly affect the organ in question, i.e., the injury is secondary to the burn.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or protecting damage to liver tissues secondary to a burn.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• Methods for assessing liver function are well known in the art and include, but are not limited to, using blood tests for serum alanine aminotransferase (ALT) levels, alkaline phosphatase (AP), or bilirubin levels.
• liver imaging e.g., MRT, ultrasound
• histological evaluation of liver biopsy e.g., MRT, ultrasound
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or protecting damage to kidney tissues secondary to a burn.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• Methods for assessing kidney function are well known in the art and include, but are not limited to, using blood tests for serum creatinine, or glomerular filtration rate. Methods for assessing deterioration of kidney structure are also well known. Such methods include kidney imaging (e.g. , MRI
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in preventing or treating hypermetabolism associated with a burn injury.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• a hypermetabolic state may be associated with hyperglycemia, protein loss, and a significant reduction of lean body mass.
• Reversal of the hypermetabolic response may be accomplished by administering acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology and by manipulating the subject's physiologic and biochemical environment through the administration of specific nutrients, growth factors, or other agents.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology may be administered to a subject suffering from a burn in order to treat or prevent hypermetabolism.
• the disclosure provides method for preventing in a subject, a burn injury or a condition associated with a burn injury, by administering acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to the subject.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology may be administered to a subject at risk of receiving burns.
• pharmaceutical compositions or medicaments of compositions of the present technology are administered to a subject susceptible to, or otherwise at risk of, a burn injury to eliminate or reduce the risk, or delay the onset of the burn injury and its complications.
• compositions or medicaments are administered to a subject already suffering from a burn injury in an amount sufficient to cure, or partially arrest, the symptoms of the injury, including its complications and intermediate pathological phenotypes in development of the disease.
• Acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology may be administered to a subject following a burn, but before the development of detectable symptoms of a systemic injury, such as organ dysfunction or failure, and thus the term "prevention" as used herein in its broadest sense and refers to a prophylactic use which completely or partially prevents systemic injury, such as organ dysfunction or failure or hypermetabolism following burns.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology can prevent or treat Metabolic Syndrome in mammalian subjects.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the Metabolic Syndrome may be due to a high-fat diet or, more generally, over-nutrition and lack of exercise.
• Acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology may reduce one or more signs or symptoms of Metabolic Syndrome, including, but not limited to, dyslipidemia, central obesity, blood fat disorders, and insulin resistance.
• Metabolic Syndrome including, but not limited to, dyslipidemia, central obesity, blood fat disorders, and insulin resistance.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Metabolic Syndrome is generally associated with type II diabetes, coronary artery disease, renal dysfunction, atherosclerosis, obesity, dyslipidemia, and essential hypertension.
• the present methods provide for the prevention and/or treatment of Metabolic Syndrome or associated conditions in a subject by administering an effective amount of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to a subject in need thereof.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• a subject may be administered acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to improve one or more of the factors contributing to Metabolic Syndrome.
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology to improve one or more of the factors contributing to Metabolic Syndrome.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in reducing the symptoms of Metabolic Syndrome.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the technology may provide a method of treating or preventing the specific disorders associated with Metabolic Syndrome, such as obesity, diabetes,
• hypertension, and hyperlipidemia in a mammal by administering acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
• the specific disorder may be obesity.
• the specific disorder may be dyslipidemia (i.e., hyperlipidemia).
• peptide conjugates of the present technology to a subject exhibiting one or more conditions associated with
• Metabolic Syndrome will cause an improvement in one or more of those conditions (e.g., an improvement in one or more of body weight, LDL cholesterol level, HDL cholesterol level, triglyceride level, oral glucose tolerance).
• a subject may exhibit at least about 5%, at least about 10%, at least about 20%, or at least about 50%> reduction in body weight compared to the subject prior to receiving the acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• a subject may exhibit at least about 5%, at least about 10%, at least about 20%, or at least about 50% reduction in LDL cholesterol and/or at least about 5%, at least about 10%, at least about 20%, or at least about 50% increase in HDL cholesterol compared to the subject prior to receiving the acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in
• a subject may exhibit at least about 5%, at least about 10%>, at least about 20%>, or at least about 50%> reduction in some triglycerides compared to the subject prior to receiving the acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the present technology provides a method for preventing, in a subject, a disease or condition associated with Metabolic Syndrome in skeletal muscle tissues, by administering to the subject acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology that modulate one or more signs or markers of metabolic syndrome, e.g., body weight, serum triglycerides or cholesterol, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt- P, IRS-P), mitochondrial function (e.g., respiration or H 2 O
• Subjects at risk for Metabolic Syndrome can be identified by, e.g., any or a combination of diagnostic or prognostic assays as described herein.
• pharmaceutical compositions or medicaments of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are administered to a subject susceptible to, or otherwise at risk for a disease or condition in an amount sufficient to eliminate or reduce the risk, or delay the onset of the disease, including biochemical, histologic and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
• Administration of the prophylactic compositions of the present technology can occur prior to the manifestation of symptoms characteristic of the aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology, which act to enhance or improve mitochondrial function can be used for treating the subject.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• compositions or medicaments of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology are administered to a subject suspected of, or already suffering from such a disease in an amount sufficient to cure, or partially arrest, the symptoms of the disease, including its complications and intermediate pathological phenotypes in development of the disease.
• the present technology provides methods of treating an individual afflicted with Metabolic Syndrome or a Metabolic Syndrome-associated disease or disorder.
• the present disclosure also contemplates combination therapies of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt- Lys-Phe-NH 2 ), or peptide conjugates of the present technology with one or more agents for the treatment of blood pressure, blood triglyceride levels, or high cholesterol.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt- Lys-Phe-NH 2
• peptide conjugates of the present technology with one or more agents for the treatment of blood pressure, blood triglyceride levels, or high cholesterol.
• Treatment for Metabolic Syndrome, obesity, insulin resistance, high blood pressure, dyslipidemia, etc. can also include a variety of other approaches, including weight loss and exercise, and dietary changes.
• dietary changes include: maintaining a diet that limits carbohydrates to 50 percent or less of total calories; eating foods defined as complex carbohydrates, such as whole grain bread (instead of white), brown rice (instead of white), sugars that are unrefined, increasing fiber consumption by eating legumes (for example, beans), whole grains, fruits and vegetables, reducing intake of red meats and poultry, consumption of "healthy" fats, such as those in olive oil, flaxseed oil and nuts, limiting alcohol intake, etc.
• treatment of blood pressure, and blood triglyceride levels can be controlled by a variety of available drugs (e.g., cholesterol modulating drugs), as can clotting disorders (e.g., via aspirin therapy) and in general, prothrombotic or proinflammatory states. If Metabolic Syndrome leads to diabetes, there are, of course, many treatments available for this disease.
• drugs e.g., cholesterol modulating drugs
• clotting disorders e.g., via aspirin therapy
• prothrombotic or proinflammatory states e.g., via aspirin therapy
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in the treatment or prevention of an ophthalmic condition.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology may treat or prevent ophthalmic diseases or conditions by reducing the severity or occurrence of oxidative damage in the eye.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• the ophthalmic condition is selected from the group consisting of: dry eye, diabetic retinopathy, cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration, and oxygen-induced retinopathy.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in reducing intracellular reactive oxygen species (ROS) in human retinal epithelial cells (HRECs).
• ROS reactive oxygen species
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in preventing the mitochondrial potential loss of HRECs treated with high-glucose.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• the ⁇ of HRECs can be measured by flow cytometry after JC-1 fluorescent probe staining. High glucose (30 mM) treatment results in a rapid loss of mitochondrial membrane potential of the cultured HRECs.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in increasing ⁇ in high glucose treated HRECs.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in reducing the elevated expression of caspase-3 in high glucose-treated HRECs.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys- Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in increasing the expression of Trx2 in the high glucose- treated HRECs.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic- cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the present methods provide for the prevention and/or treatment of an ophthalmic condition in a subject by administering an effective amount of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in
• compositions comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in
• an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology to improve one or more of the factors contributing to an ophthalmic disease or condition.
• compositions or medicaments comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject known to have or suspected of having a disease, in an amount sufficient to cure, or at partially arrest/reduce, the symptoms of the disease, including complications and intermediate pathological phenotypes in development of the disease.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the disclosure provides methods of treating an individual afflicted with an ophthalmic condition.
• the technology provides a method of treating or preventing specific ophthalmic disorders, such as diabetic retinopathy, cataracts, retinitis pigmentosa, glaucoma, choroidal neovascularization, retinal degeneration, and oxygen- induced retinopathy, in a mammal by administering acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing diabetic retinopathy in a subject.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• D-Arg-2'6'-Dmt-Lys-Phe-NH 2 an aromatic-cationic peptide
• microvascular obstructions cause cotton wool patches to form on the retina.
• retinal edema and/or hard exudates may form in individuals with diabetic retinopathy due to increased vascular hyperpermeability.
• diabetic retinopathy includes, but are not limited to, difficulty reading, blurred vision, sudden loss of vision in one eye, seeing rings around lights, seeing dark spots, and/or seeing flashing lights.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing cataracts in a subject.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Cataracts are a congenital or acquired disease characterized by a reduction in natural lens clarity. Individuals with cataracts may exhibit one or more symptoms, including, but not limited to, cloudiness on the surface of the lens, cloudiness on the inside of the lens, and/or swelling of the lens.
• Typical examples of congenital cataract- associated diseases are pseudo-cataracts, membrane cataracts, coronary cataracts, lamellar cataracts, punctuate cataracts, and filamentary cataracts.
• Typical examples of acquired cataract-associated diseases are geriatric cataracts, secondary cataracts, browning cataracts, complicated cataracts, diabetic cataracts, and traumatic cataracts.
• Acquired cataracts are also inducible by electric shock, radiation, ultrasound, drugs, systemic diseases, and nutritional disorders. Acquired cataracts further include postoperative cataracts.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing retinitis pigmentosa in a subject.
• retinitis pigmentosa also present with a variety of symptoms including, but not limited to, headaches, numbness or tingling in the extremities, light flashes, and/or visual changes. See, e.g., Heckenlively, et al, Am. J.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing glaucoma in a subject.
• acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Glaucoma is a genetic disease characterized by an increase in intraocular pressure, which leads to a decrease in vision. Glaucoma may emanate from various ophthalmologic conditions that are already present in an individual, such as, wounds, surgery, and other structural malformations.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing macular degeneration in a subject.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Macular degeneration is typically an age-related disease. The general categories of macular degeneration include wet, dry, and non-aged related macular degeneration.
• Dry macular degeneration which accounts for about 80-90 percent of all cases, is also known as atrophic, nonexudative, or drusenoid macular degeneration.
• drusen typically accumulate beneath the retinal pigment epithelium tissue. Vision loss subsequently occurs when drusen interfere with the function of photoreceptors in the macula.
• Symptoms of dry macular generation include, but are not limited to, distorted vision, center-vision distortion, light or dark distortion, and/or changes in color perception. Dry macular degeneration can result in the gradual loss of vision.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe- NH 2
• CNV Choroidal neovascularization
• Symptoms of CNV include, but are not limited to, seeing flickering, blinking lights, or gray spots in the affected eye or eyes, blurred vision, distorted vision, and/or loss of vision.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing retinal degeneration in a subject.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• Retinal degeneration is a genetic disease that relates to the break-down of the retina.
• Retinal tissue may degenerate for various reasons, such as, artery or vein occlusion, diabetic retinopathy, retinopathy of prematurity, and/or retrolental fibroplasia.
• Retinal degradation generally includes retinoschisis, lattice degeneration, and is related to progressive macular degeneration.
• the symptoms of retina degradation include, but are not limited to, impaired vision, loss of vision, night blindness, tunnel vision, loss of peripheral vision, retinal detachment, and/or light sensitivity.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful in treating or preventing oxygen-induced retinopathy in a subject.
• Oxygen-induced retinopathy is a disease characterized by microvascular degeneration. OIR is an established model for studying retinopathy of prematurity. OIR is associated with vascular cell damage that culminates in abnormal neovascularization.
• Oxidative stress also plays an important role in the development of OIR where endothelial cells are prone to peroxidative damage. Pericytes, smooth muscle cells, and perivascular astrocytes, however, are generally resistant to peroxidative injury. See, e.g., Beauchamp, et al., J. Appl. Physiol. 90:2279-2288 (2001).
• OIR including retinopathy of prematurity, is generally asymptomatic. However, abnormal eye movements, crossed eyes, severe nearsightedness, and/or leukocoria, can be a sign of OIR or retinopathy of prematurity.
• the present technology provides a method for preventing an ophthalmic condition in a subject by administering to the subject an effective amount of acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in
• an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology that modulates one or more signs or markers of an ophthalmic condition.
• Subjects at risk for an ophthalmic condition can be identified by, e.g., any or a combination of diagnostic or prognostic assays as described herein.
• compositions or medicaments comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are administered to a subject susceptible to, or otherwise at risk of a disease or condition in an amount sufficient to eliminate or reduce the risk, or delay the onset of the disease, including biochemical, histologic and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are useful for both prophylactic and therapeutic methods of treating a subject having or at risk of (susceptible to) heart failure.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• the present methods provide for the prevention and/or treatment of heart failure in a subject by administering an effective amount of acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to a subject in need thereof.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) or peptide conjugates of the present technology are used to treat or prevent heart failure by enhancing mitochondrial function in cardiac tissues.
• acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof e.g., Ac* and/or PSMc*
• one or more active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• compositions or medicaments comprising acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are examples of one or more active agents (e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology are examples of the present technology.
• active agents e.g., an aromatic-cationic peptide such as D- Arg-2'6'-Dmt-Lys-Phe-NH 2
• the present technology provides methods of treating an individual afflicted with heart failure.
• Subjects suffering from heart failure can be identified by any or a combination of diagnostic or prognostic assays known in the art.
• typical symptoms of heart failure include shortness of breath (dyspnea), fatigue, weakness, difficulty breathing when lying flat, and swelling of the legs, ankles, or abdomen (edema).
• the subject may also be suffering from other disorders including coronary artery disease, systemic hypertension, cardiomyopathy or myocarditis, congenital heart disease, abnormal heart valves or valvular heart disease, severe lung disease, diabetes, severe anemia hyperthyroidism, arrhythmia or dysrhythmia and myocardial infarction.
• AMI Acute myocardial infarction
• the present technology provides a method of treating hypertensive cardiomyopathy by administering an effective amount of acrylamido compounds, phenyl- substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology to a subject in need thereof.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• hypertensive cardiomyopathy can be identified by any or a combination of diagnostic or prognostic assays known in the art.
• typical symptoms of hypertensive cardiomyopathy include hypertension (high blood pressure), cough, weakness, and fatigue.
• Additional symptoms of hypertensive cardiomyopathy include leg swelling, weight gain, difficulty breathing when lying flat, increasing shortness of breath with activity, and waking in the middle of the night short of breath.
• the present technology provides a method for preventing heart failure in a subject by administering to the subject acrylamido compounds, phenyl-substituted maleimide compounds, or derivatives, analogues, or pharmaceutically acceptable salts thereof (e.g., Ac* and/or PSMc*) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology that prevent the initiation or progression of the infarction.
• active agents e.g., an aromatic-cationic peptide such as D-Arg-2'6'-Dmt-Lys-Phe-NH 2
• peptide conjugates of the present technology that prevent the initiation or progression of the infarction.

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Cited By (4)

• 2015
  • 2015-03-11 WO PCT/US2015/019930 patent/WO2016144352A2/fr not_active Ceased

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