WO2020106773A1 - Traitement du syndrome du côlon irritable - Google Patents

Traitement du syndrome du côlon irritable

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Publication number
WO2020106773A1
WO2020106773A1 PCT/US2019/062294 US2019062294W WO2020106773A1 WO 2020106773 A1 WO2020106773 A1 WO 2020106773A1 US 2019062294 W US2019062294 W US 2019062294W WO 2020106773 A1 WO2020106773 A1 WO 2020106773A1
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Prior art keywords
alkyl
aryl
compound
aminocarbonyl
pain
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English (en)
Inventor
Daniela Salvemini
Carla Ghelardini
Lorenzo Di Cesare MANNELLI
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St Louis University
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St Louis University
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present disclosure generally relates to the field of medicine. Specifically, the present disclosure is directed to the use of a drug that is a selective agonist for the human adenosine A3 receptor (A3AR) subtype for the treatment of Irritable Bowel Syndrome (IBS). Treatment with a selective agonist for the A3AR reduces and/or prevents the abdominal pain and discomfort observed in patients with Irritable Bowel Syndrome (IBS).
  • A3AR human adenosine A3 receptor
  • IBS Irritable bowel syndrome
  • GI organic gastrointestinal
  • the cause of IBS is unknown but is likely to be multifactorial. In particular, it is unclear whether pain mechanisms are fundamentally different in the different subtypes, although it may be that the pain of IBS-C comes from both the constipation itself and the pain mechanism(s) that are present in other subtypes.
  • the variable presentation of bowel function on the background of a similar pain/discomfort complaint suggests that the bowel disorders are not the primary pathophysiological phenomena.
  • the available evidence indicates that the pain of IBS is due to a neuroinflammatory effect mediated by increased levels of pro- inflammatory cytokines acting on the enteric nervous system and/or the bowel’s sensory innervation.
  • linaclotide an activator of guanylate cyclase-C which stimulates cyclic guanosine monophosphate (cGMP) level and thus increases fluid secretion and mobility.
  • cGMP cyclic guanosine monophosphate
  • linaclotide improved abdominal pain and increased bowel movements (34% vs. 21% for placebo).
  • the number needed to treat (NNT, the average number of patients needed to treat in order to obtain one patient with significant clinical benefit) is 7.7, which indicates that a large percentage of patients are not helped by linaclotide. It is not known whether linaclotide is effective in other IBS subtypes. There is anecdotal evidence for at least some pain relief with a large number of treatments, but none of these has been tested rigorously.
  • adenosine is a major neuroprotective molecule, and that nerve cells, glia and other cell types express receptors on their membranes that have adenosine as their natural ligand.
  • G- protein-coupled receptor subtypes for adenosine AiAR, A2AAR, A2BAR, and A3AR (A3AR).
  • Drug-like molecules are known that have selectivity for binding to each of the four subtypes.
  • highly-selective (greater than 10,000-fold relative to each of the other three subtypes) agonists for the A3AR are available.
  • Drugs that selectively activate the A3AR are advantageous because they avoid the cardiovascular, renal and immunological side-effects that are produced by activation of the other three receptor subtypes.
  • Visceral pain management is a major clinical problem, because of the lack of effective and safe drugs.
  • Abdominal pain may be the most common form of visceral hypersensitivity and may often be the result of inflammatory bowel diseases.
  • intestinal barrier function In some cases, when the gut is inflamed, there may be breakdown of intestinal barrier function, abnormal secretion, changes in the patterns of motility, and altered visceral sensation which altogether contribute to generation of symptoms (diarrhoea, cramping, and pain, etc).
  • pain may persist beyond the relief of inflammation. This may reveal a peculiar kind of chronic hypersensitivity thought to be due to inflammatory, immune and neuropathic mechanisms.
  • the most efficacious therapies against visceral hypersensitivity are mainly directed toward treating bowel dysfunction, while drugs able to directly target the associated pain are still unsatisfactory.
  • the neuromodulator adenosine may exert potent and long-lasting pain suppression in preclinical models as well as in human studies. Moreover, the adenosinergic signalling may be known to modulate intestinal functionality. In some cases, it was thought that the analgesic effects of adenosine were mediated by activation of the Ai adenosine receptor (AiAR). In some cases, research efforts over the last several years may have implicated a key role for the A3AR subtype. For example, A3AR agonists may be able to block the development of trauma- and chemotherapeutic-induced neuropathic pain and may be also effective in reducing inflammatory and cancer-related pain.
  • AiAR Ai adenosine receptor
  • selective A3AR stimulation may inhibit the opening of N-type voltage-gated Ca 2+ channels (Ca v 2.2) and may decrease the electrically-evoked excitation of isolated rat dorsal root ganglia (DRG) neurons.
  • DRG isolated rat dorsal root ganglia
  • this mechanism could explain the anti-hyperalgesic effect of A3AR agonists across different models.
  • therapeutic targeting of AiAR has been limited to severe cardiovascular side effects; in contrast, A3AR agonists are already in advanced clinical trials for different indications with a good safety profile.
  • FIGs. 1A-D depict the effect of MRS5980 on post-inflammatory visceral pain induced by dinitrobenzene sulfonic acid (DNBS).
  • DNBS dinitrobenzene sulfonic acid
  • FIGs. 2A-D depict the evaluation of the role of adenosine A3AR.S and N-type voltage-gated calcium channels in visceral pain relief and comparison with the effect of reference drugs.
  • FIGs. 3A-B illustrate the effect of MRS5980 on persistent visceral pain induced by DNBS injection.
  • FIGs. 4A-B depict that the gastro-intestinal transit may not be reduced by acute A3AR agonism with MRS5980.
  • FIGs. 5A-E illustrate the electrophysiological properties of DRG neurons isolated from control or DNBS-treated rats.
  • FIGs. 6A-E depict the effects of the adenosine A3R agonists Cl-IB-MECA and MRS5950 on voltage-gated Ca 2+ currents in isolated DRG neurons.
  • FIG. 7 depict the effect of MRS5980 on post-inflammatory visceral pain induced by dinitrobenzene sulfonic acid (DNBS).
  • DNBS dinitrobenzene sulfonic acid
  • salts or“pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, 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, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • phrases“pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term“prevent” or“preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • treat may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the present disclosure is directed to methods for treating the pain and discomfort of Irritable Bowel Syndrome by administering a selective agonist for the adenosine A3 human receptor subtype to a patient in need thereof.
  • a compound may be a selective A3AR agonist using known methods, including competitive radioimmunoassays and assays of forskolin-stimulated cyclic adenosine monophosphate (cAMP) production in human A3AR transfected CHO cells or HEK cells.
  • cAMP forskolin-stimulated cyclic adenosine monophosphate
  • “Selective” is herein defined as binding affinity (or cAMP production) for the human A3 receptor subtype that is at least 50-fold greater than the binding affinity (or cAMP production) for any of the other three types of human receptor subtype.
  • suitable selective agonists for the human A3AR may be chosen from, but not limited to, any of the following: (i) N 6 -benzyladenosine-5’-N- methyluronamides such as N 6 -(3-iodobenzyl)-adenosine-5’-N-methyluronamide (also known as IB-MECA), and 2-Chloro-N 6 -(3-iodobenzyl)-adenosine-5’-N-methyluronamide (also known as 2-CI-IB-MECA); (ii) (N)-methanocarba nucleosides such as (lR,2R,3S,4R)-4-(2- chloro-6-((3-chlorobenzyl)amino)-9H-purin-9-yl)-2,3-di-hydroxy-N- methylbicyclo[3.1.0]hexane-l -carboxamide (also known as CF502, Can
  • the A3AR agonist is a compound of the formula (I):
  • Y is N or CH
  • R 1 is selected from C1-C 6 alkyl, C1-C 6 alkoxy, hydroxyl, C3-C8 cycloalkyl, C 6 -C14 aryl C 3 -C8 cycloalkyl, C 3 -C8 cycloalkyl C1-C 6 alkyl, C 3 -C8 dicycloalkyl C1-C 6 alkyl, C7-C12 bicycloalkyl, C7-C12 bicycloalkyl C1-C 6 alkyl, C7-C14 tricycloalkyl C1-C 6 alkyl, C 6 -C14 aryl, C 6 -C14 aryl C1-C 6 alkyl, C 6 -C14 diaryl C1-C 6 alkyl, C 6 -C14 aryl C1-C 6 alkoxy, heterocyclyl Ci- Ce alkyl, heterocyclyl, 4-[[[4-[[[[(2-amino C1-C 6
  • R 2 is selected from C 6 -C12 aryl, C 3 -C8 cycloalkyl, heteroaryl, and metallocenyl, wherein the aryl group is substituted with one or more substituents selected from trifluoromethyl, hydroxyalkyl, alkoxy, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, arylcarbonyl, and any combination thereof, wherein the heteroaryl group is optionally substituted with one or more substituents selected from halo, trifluoromethyl, amino, alkyl, hydroxyalkyl, aryl, benzo, alkoxy, hydroxyl, carboxyl, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, alkylcarbonyl, arylcarbonyl, and any combination thereof; R 3 and R 4 are independently selected from hydrogen, hydroxyl, amino, mercapto, ureido, C1-C6
  • R 5 is selected from C1-C3 alkyl aminocarbonyl, di(Ci-C 3 alkyl) aminocarbonyl, C1-C3 alkylthio C1-C3 alkyl, halo C1-C3 alkyl, hydrazinyl, amino C1-C3 alkyl, hydroxy C1-C3 alkyl, C3-C6 cycloalkylamino, hydroxylamino, and C2-C3 alkenyl; and
  • R 6 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and C1-C6 aminoalkyl.
  • X is NHR 1
  • R 1 is C1-C6 alkyl
  • R 2 is C6-C10 aryl, wherein the aryl group is substituted with one or more substituents selected from halo, trifluoromethyl, hydroxyalkyl, alkoxy, and any combination thereof, or R 2 is heteroaryl, and the heteroaryl group is optionally substituted with one or more substituents selected from halo, hydroxy, and alkyl.
  • R 1 is methyl
  • R 3 and R 4 are both hydroxyl
  • R 6 is hydrogen
  • R 5 is methylaminocarbonyl
  • R 2 is not 2- pyridyl or phenyl.
  • a compound or salt of formula (I) is racemic or one or more of the stereocenters has the opposite configuration relative to the structure as depicted.
  • R 6 is hydrogen
  • Y is N.
  • Y is CH.
  • R 3 and R 4 are each hydroxyl.
  • R 5 is selected from C1-C3 alkyl aminocarbonyl or di(Ci-C 3 alkyl) aminocarbonyl. In certain embodiments, R 5 is
  • X is NHR 1 .
  • R 1 is C1-C6 alkyl.
  • R 1 is selected from -CFb, - CH2CH3, and -CH2CH2CH3
  • R 2 is C6-C10 aryl, wherein the aryl group is substituted with one or more substituents selected from halo, trifluoromethyl, hydroxyalkyl, alkoxy, and any combination thereof.
  • R 2 is heteroaryl, and the heteroaryl group is optionally substituted with one or more substituents selected from hydroxy, halo and alkyl.
  • R 2 is heteroaryl selected from furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzofuranyl, and the heteroaryl group is optionally substituted with one or more substituents selected from halo, hydroxy, and alkyl.
  • R 2 is furanyl optionally substituted with one or more substituents selected from halo, hydroxy, and alkyl.
  • the compound of formula (I) is selected from:
  • the compound of Formula (I) is selected from:
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • the A3AR agonist is a compound of the formula (II):
  • Y is N or CH
  • R 101 is selected from C1-C 6 alkyl, C1-C 6 alkoxy, hydroxyl, C3-C8 cycloalkyl, C 6 -C14 aryl C3-C8 cycloalkyl, C 3 -C8 cycloalkyl C1-C 6 alkyl, C 3 -C8 di cycloalkyl C1-C 6 alkyl, C7-C12 bicycloalkyl, C7-C12 bicycloalkyl C1-C 6 alkyl, C7-C14 tricycloalkyl C1-C 6 alkyl, C 6 -C14 aryl, C 6 -C14 aryl C1-C 6 alkyl, C 6 -C14 diaryl C1-C 6 alkyl, C 6 -C14 aryl C1-C 6 alkoxy, heterocyclyl Ci- Ce alkyl, heterocyclyl, 4-[[[4-[[[[(2-amino C1-C 6
  • Z is halo, azido, or a group of the formula: N N wherein R 102 is selected from C 6 -C12 aryl, C 6 -C12 aryl-Ci-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, and metallocenyl, wherein the aryl group is optionally substituted with one or more substituents selected from trifluoromethyl, hydroxyalkyl, alkoxy, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, arylcarbonyl, and any combination thereof, wherein the heteroaryl group is optionally substituted with one or more substituents selected from halo, trifluoromethyl, amino, alkyl, hydroxyalkyl, aryl, alkoxy, hydroxyl, carboxyl, sulfonyloxy, carboxyalkyl, sulfonyloxyalkyl, alkylcarbonyl, arylcarbony
  • R 103 and R 104 are independently selected from hydrogen, hydroxyl, amino, mercapto, ureido, C1-C6 alkyl carbonylamino, hydroxy C1-C6 alkyl, and hydrazinyl;
  • R 105 is selected from hydrogen, C1-C 3 alkyl aminocarbonyl, di(Ci-C3 alkyl) aminocarbonyl, C1-C 3 alkylthio C1-C 3 alkyl, halo C1-C 3 alkyl, hydrazinyl, amino C1-C 3 alkyl, hydroxy C1-C 3 alkyl, C3-C 6 cycloalkylamino, hydroxylamino, and C2-C 3 alkenyl; and
  • R 106 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and C1-C6 aminoalkyl.
  • a compound or salt of formula (II) is racemic or one or more of the stereocenters has the opposite configuration relative to the structure as depicted.
  • R 104 are both hydroxyl, R 105 is methylaminocarbonyl, R 106 is hydrogen, X is NHMe, and Y is CH, then Z is not iodo.
  • R 106 is hydrogen
  • Y is N.
  • R 105 is selected from Ci-
  • R 103 and R 104 are both hydroxyl.
  • X is NHR 101 .
  • R 101 is C1-C 6 alkyl.
  • R 101 is C1-C 6 alkyl or C 3 -C8 cycloalkyl.
  • R 102 is C6-C10 aryl, wherein the aryl group is substituted with one or more substituents selected from
  • R 102 is heteroaryl, and the heteroaryl group is optionally substituted with one or more substituents selected from halo, hydroxy, and alkyl.
  • the compound of formula (II) is selected from:
  • the compound is:
  • a compound of Formula (II) is selected from:
  • R 102 is C6-C10 aryl, wherein the aryl group is substituted with one or more substituents selected from trifluoromethyl, hydroxyalkyl, alkoxy, and any combination thereof; or
  • R 102 is heteroaryl, and the heteroaryl group is optionally substituted with one or more substituents selected from halo, hydroxy, and alkyl.
  • a compound of Formula (II) is selected from:
  • a compound of the methods described herein is selected from Tables 1 to 4.
  • particularly suitable highly-selective ( ⁇ 10, 000-fold) A3AR agonists for use in the methods include but are not limited to, the adenosine methanocarba derivatives described in Tosh et al. (2014; 2015a, 2015b, 2015c, and 2016).
  • A3AR agonists may be selected from a compound described in any one of US Patent Nos. 9,963,450; 8,916,570; 8,735,407; 8,796,291; 9,181,253; and 9,123,131; and US Patent Application No. 20170002007, the compounds and chemical genuses of each of which are incorporated herein by reference.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.
  • A“tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, U C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium (3 ⁇ 4), iodine-125 ( 125 I) or carbon-14 ( 14 C). Isotopic substitution with 2 H, U C, 13 C, 14 C, 15 C, 12 N, 13 N,
  • the compounds disclosed herein have some or all of the 3 ⁇ 4 atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1- 2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • a“prodrug” refers to a pharmacologically less active derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the more active parent drug.
  • Prodrugs are variations or derivatives of the parent drugs which have groups cleavable under metabolic conditions. Prodrugs become the parent drugs which are pharmaceutically active in vivo , when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrugs may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active parent drug within the organism, and indicating the number of functionalities present in a precursor-type form.
  • Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. See, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985; Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992; and Burger’s Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982 (1995).
  • the A3AR agonist may be formulated according to any generally known pharmaceutical method (Remington & Gennaro, 2015) that is appropriate for the intended route of administration, including any generally known and appropriate vehicle, salt, hydrate, carrier or in any appropriate molecular precursor form (z.e., pro-drug).
  • a particularly suitable formulation includes a formulation in which the A3AR agonist is formulated in a manner intended to promote transfer across the blood-brain-barrier via any method known to one skilled in the art.
  • suitable dosage includes about 0.1 mg to about 1.0 gram per day per patient (nominally weighing 60 kilograms) or equivalent amounts calculated on the basis of milligrams per kilogram of body weight, or on the basis of milligram per meter- squared of body surface area.
  • suitable routes of administration include any standard drug administration method, including injections via the intravenous, intramuscular, subcutaneous, and intrathecal routes; inhalation (nasal or oral); per os; per rectum; and transcutaneous methods (patches, ointments, salves, etc.).
  • Drug may be administered via bolus one to four times a day, or via any slow release method that yields a plasma drug level above the therapeutic threshold.
  • the therapeutically effective amount is from 0.1 mg to 1.0 gram per day per patient (nominally weighing 60 kilograms) or equivalent amounts calculated on the basis of milligrams per kilogram of body weight, or on the basis of milligram per meter-squared of body surface area.
  • the appropriate dosage can vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • suitable subjects include non-human animals, such as, for example, nematodes, mammals, non-human primates, rodents (e.g., mice, rats, and hamsters), stock and domesticated animals (e.g., pigs, cows, sheep, horses, cats, and dogs), and birds.
  • Particularly suitable subjects include humans.
  • “subject in need thereof’ also used interchangeably herein with“a patient in need thereof’ and“an individual in need thereof’ refers to a subject susceptible to or at risk of a specified disease, disorder, or condition. More particularly, in the present disclosure the methods of can be used with an individual or subset of individuals who have, are susceptible to, and at elevated risk for experiencing irritable bowel syndrome.
  • the methods of can also be used with an individual or subset of individuals who have, are susceptible to, and at elevated risk for experiencing pain associated with or co-extensive with irritable bowel syndrome.
  • Individuals may be susceptible to or at elevated risk for these diseases, disorders or conditions due to family history, age, environment, and/or lifestyle.
  • “susceptible” and“at risk” refer to having little resistance to a certain disease, disorder or condition, including being genetically predisposed, having a family history of, and/or having symptoms of the disease, disorder or condition.
  • the effective amount may be given via any standard drug administration method, including but not limited to injections via the intravenous, intramuscular, subcutaneous, and intrathecal routes; via inhalation (nasal or oral); per os; per rectum; or via transcutaneous methods (patches, ointments, salves, etc.).
  • the A3AR agonist may be formulated according to any generally known pharmaceutical method (Remington & Gennaro, 2015) that is appropriate for the intended route of administration, including any generally known and appropriate vehicle, salt or hydrate, or in any appropriate molecular precursor form (i.e., pro-drug).
  • the A3AR agonist is formulated in a manner intended to promote transfer across the blood-brain-barrier via any method known to one skilled in the art.
  • the A3AR agonist of the present disclosure can be administered to animals, preferably to mammals, and in particular to humans as therapeutics per se, as mixtures with one another or in the form of pharmaceutical preparations, and which as active constituent contains an effective dose of the compositions, in addition to customary pharmaceutically innocuous excipients and additives.
  • the active ingredients can be introduced in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • Pharmaceutically acceptable carriers, and, optionally, other therapeutic and/or prophylactic ingredients must be“acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • the A3AR agonist may be given on a daily basis (once, twice, three times or 4 times per day) to a patient diagnosed with any subtype of IBS.
  • A3AR receptors may demonstrate to be a pharmacological target for relieving visceral pain.
  • MRS5980 and Cl-IB-MECA may be effective against post-inflammatory visceral hypersensitivity in rats.
  • the intra-colonic injection of 2,4-dinitrobenzenesulfonic acid (DNBS) in rodents may induce a long-lasting visceral hypersensitivity which may be measured with high reproducibility as a lowered sensory threshold to colorectal distension.
  • DNBS-induced visceral hypersensitivity may persist after the resolution of the acute inflammatory phase making this model suitable to investigate visceral pain related related to IBD or IBS.
  • IBS may be a chronic disease characterized by a marked abdominal pain in the absence of histopathological explanations.
  • the administration of A3AR agonists in the model of post- inflammatory visceral pain may demonstrate an efficacy equivalent to that of linaclotide, an approved treatment for reducing abdominal pain (and also abdominal bloating, and bowel symptoms) in adult patients suffering from IBS with predominant constipation.
  • the trinitrobenzenesulfonic acid (TNBS)-induced model may be used in preclinical studies to identify the potential clinical utility of linaclotide.
  • linaclotide, a selective agonist of the guanylate cyclase-2C that is expressed on the luminal surface of intestinal enterocytes may reduce intestinal pain in animal models.
  • linaclotide may be associated with the development of diarrhoea in 20% of patients. In some cases, this adverse effect may make linaclotide unsuitable for patients affected by diarrhoea-predominant IBS or IBS with alternating constipation and diarrhoea.
  • A3AR may be known to participate in the regulation of enteric neuromuscular function and may be upregulated in the stomach, jejunum, colon ileum, and cecum during colitis.
  • experiments may be performed as described elsewhere herein.
  • 70kDa FITC-dextran may reveal that MRS5980 does not impair gastrointestinal transit as compared to vehicle.
  • these results may indicate that the antihyperalgesic efficacy of MRS5980 in visceral pain condition may not be associated to motility alteration. In some cases, this may suggest a mechanism related to sensitivity modulation rather than spasmolytic activity.
  • the efficacy of A3AR agonists against visceral pain may be consistent with data showing that the A3AR may be involved with multiple pain mechanisms at peripheral, spinal and supraspinal levels.
  • A3AR agonists may be anti-hyperalgesic against neuropathic pain via inhibition of the astrocyte-associated neuroinflammatory response in the spinal cord, a phenomenon that may be strongly involved in pain persistence.
  • A3AR activation may enhance the formation of anti-inflammatory cytokines and the production of glial-derived neuroprotective substances.
  • in vitro and in vivo studies may demonstrate that A3AR may produce its effects by inhibiting the p38 MAPK and NF-KB signaling pathways and inflammasome activity.
  • A3AR activation may reduce colitis-induced tissue injury by modulating the NF-KB signalling pathway and through inhibiting NLRP3 inflammasome activation and pyroptosis in human colonic epithelial cells.
  • A3AR.S may limit excitatory neurotransmission, which may be altered in chronic as well as in visceral pain.
  • the protective role of A3ARS in the first phase of ischemia may appear to be related to a decrease in synaptic transmission.
  • A3AR activation may protect against the neurotoxic intra-cellular Ca 2+ rise mediated by P2X7 or NMDA receptors.
  • selective A3 AR stimulation may inhibit N-type Ca v 2.2 opening in isolated rat DRG neurons.
  • both Cl-IB-MECA and/or MRS5980 may significantly inhibit Ca v 2.2 activation in DRG neurons of DNBS -treated rats.
  • the effect may be prevented by the selective A3AR antagonist, MRS1523, and by the Ca v 2.2 blocker, PD173212. This may confirm the involvement of Ca v 2.2 in the A 3 AR-mediated effect.
  • a significant difference between A 3 AR-mediated inhibition in DRG neurons isolated from DNBS-treated us vehicle-treated animals may not be measured.
  • alterations in passive membrane properties and steady-state Ca 2+ currents may be observed between the two groups.
  • the resting membrane potential may be significantly more depolarized in DRG neurons isolated from DNBS-treated animals. In some cases, this may suggest a hyperexcitable state in inflamed animals. In some cases, steady-state Ca 2+ currents, but not peak Ca 2+ currents, may be markedly reduced in DRG neurons isolated from DNBS animals. In some cases, a decrease in sustained Ca 2+ influx into the cell may lead to membrane potential instability and depolarization through a decrease of Ca 2+ -activated K + channel (Kca) opening. In some cases, Ca 2+ -activated K + channel may be known to stabilize the membrane potential and may participate in repolarizing neurons after action potential firing, thus avoiding bursting activity.
  • Ca v 2.2 may induce a voltage-dependent.
  • Ca 2+ independent ATP secretion from the soma of DRG neurons may be Ca 2+ independent ATP secretion from the soma of DRG neurons.
  • ATP may be a powerful mediator of pain, for example, ATP -induced activation of the P2X3 receptor is involved in visceral pain, as shown by the ability of the P2X3 antagonist, A-317491, may potently reduce hypersensitivity.
  • Ca v 2.2-mediated modulation may contribute to A3AR- mediated anti-hyperalgesia. Modulation of Ca v 2.2 channel activity may be implied in the pharmacodynamics of pain-relieving compounds, such as other Gi-coupled receptor agonists, e.g., opioids, cannabinoids, neuropeptide Y, and substance P. Also, the neuropathic pain analgesics, gabapentin and pregabalin, may inhibit Ca v 2.2-mediated synaptic transmission. Gabapentinoids may be effective in reducing visceral pain and may prevent spinal neuronal activation associated with colorectal distension in animals and may be used to treat for IBS.
  • Gi-coupled receptor agonists e.g., opioids, cannabinoids, neuropeptide Y, and substance P.
  • the neuropathic pain analgesics, gabapentin and pregabalin may inhibit Ca v 2.2-mediated synaptic transmission. Gabapentin
  • a direct inhibitor of Ca v 2.2 channel activity, ziconotide may be currently used clinically for pain therapy, although it may be limited to the intrathecal route.
  • the i.p. administration of the specific Ca v 2.2 inhibitor PD173212 may significantly decrease visceral hypersensitivity in DNBS-treated animals.
  • A3AR agonists may appear to be a promising resource for visceral pain management.
  • compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims
  • Example 3 Assessment of visceral sensitivity by Viscero-Motor Response
  • VMR viscero-motor response
  • EMG electromyography
  • CCD colorectal distension
  • the EMG signal consequent to colorectal stimulation was recorded, amplified and filtered, digitised, and analysed and quantified.
  • AUC area under the curve
  • the time elapsed between two consecutive distension was 5 min, the entire protocol lasted 45 min.
  • the measurements were carried out 14 and 21 days after DNBS administration.
  • Behavioral responses to CRD were assessed via Abdominal Withdrawal Reflex (AWR) measurement in conscious animals using a semi-quantitative score. Briefly, rats were anesthetized with isoflurane, and a lubricated latex balloon (length: 4.5 cm), attached to polyethylene tubing, assembled to an embolectomy catheter and connected to a syringe filled with water was inserted through the anus into the rectum and descending colon of adult rats. The tubing was taped to the tail to hold the balloon in place. Then rats were allowed to recover from the anaesthesia for 30 min.
  • AWR Abdominal Withdrawal Reflex
  • AWR measurement consisted of visual observation of animal responses to graded CRD (0.5, 1, 2, 3 mL) by blinded observers who assigned AWR scores: No behavioural response to colorectal distention (0); Immobile during colorectal distention and occasional head clinching at stimulus onset (1); Mild contraction of the abdominal muscles but absence of abdomen lifting from the platform (2); Observed strong contraction of the abdominal muscles and lifting of the abdomen off the platform (3); Arching of the body and lifting of the pelvic structures and scrotum (4). The measurements were carried out 14, 21, 28 and 35 days after DNBS administration.
  • Example 5 Upper gastro-intestinal transit treatment and harvesting.
  • intestine was sectioned into 10 equal lengths and placed in pre weighed 15 ml centrifuge tubes containing 1 ml IX PBS (prepared in house); tubes were re-weighed to obtain weight of each intestinal section. Samples were then placed on ice and homogenized for 45 seconds (s) in 1 milliter (ml) IX PBS. Homogenized samples were then centrifuged for 15 min at 14,000 RPM with the supernatant decanted into a new identically labeled tube for fluorescence reading. A FITC-dextran standard was prepared (1250, 937.5, 625, 437.5, 312.5, 187.5, 62.5, 0 pg/ml) in duplicate.
  • N-[[4- (1,1 -dimethylethyl)phenyl]methyl]-N-methyl-L-leucyl-N-( 1 , 1 -dimethyl ethyl)-0- (phenylmethyl)-L-tyrosinamide (PD 173232) were dissolved in 5% DMSO and 5% TWEEN 20 saline solution for in vivo administration.
  • Linaclotide was dissolved in water and orally administered 1 h before starting the behavioural tests.
  • Cl-IB-MECA, MRS5980 and PD173232 were administered i.p. 15 min before the test.
  • MRS 1523 was administered i.p. 15 min before Cl-IB-MECA and MRS5980.
  • Gastro-intestinal transit study the compound MRS5980 was dissolved in 5 % DMSO, and then suspended in saline. MRS5980 and vehicle were administered via i.p, injection to all animals in study at 2.4 pmol kg 1 body weight (1 ml/kg injection volume). 70 kDa FITC-dextran (Sigma) was dosed by oral gavage at a concentration of 5 mg/mL, 300 pL per rat.
  • Primary DRG neurons (related to colon sensitive innervations: T12, T13, L4, L5, L6, SI, S2) were isolated from sham operated- or DNBS-treated (at 14 th day) rats and cultured. Briefly, ganglia were bilaterally excised and enzymatically digested using 2 mg/ml of collagenase type 1A and 1 mg/ml of trypsin in Hank’s Balanced Salt Solution (HBSS) (25-35 min at 37 °C).
  • HBSS Balanced Salt Solution
  • DMEM Dulbecco’s Modified Eagle’s Medium
  • FBS heat-inactivated fetal bovine serum
  • mice neuronal growth factor NGF
  • cytosine- -D-arabino-furanoside free base 13 mm glass coverslips coated with poly-L-lysine (8.3 mM) and laminin (5 mM).
  • DRG neurons were cultured for 1-2 days before being used for experiments.
  • Borosilicate glass electrodes were pulled to a final tip resistance of 1.5-3 MW.
  • Passive membrane properties of DRG neurons isolated from control or DNBS-treated rats were investigated under physiological-like conditions by using the following K-gluconate- based pipette solution (mM): KGlu 130; NaCl 4.8; KC1 10; MgCb 2; CaCb 1; Na 2 -ATP 2; Na 2 -GTP 0.3; EGTA 3; HEPES 10 (pH 7.4 with KOH).
  • Resting membrane potential (Vm) was measured immediately after seal break-through by switching the amplifier to the current- clamp mode.
  • the calculated liquid junction potential for K-gluconate pipettes in our experimental conditions was 15.0 mV and Vm values reported in the present research have been corrected accordingly.
  • VDCCs Voltage-dependent Ca 2+ currents
  • CsCl 130); NaCl (4.8); KC1 (10); MgCb (2); CaCb (1); Na 2 -ATP (2); Na 2 -GTP (0.3); EGTA (3); and HEPES (10 - pH 7.4 with CsOH).
  • the extracellular solution was (in mM): NaCl (147); CsCl (4); MgCb (1); and CaCb (5); HEPES (10); D-glucose (10); pH 7.4 with NaOH.
  • Tetrodotoxin 1 mM
  • 5-(4- butoxy-3-chlorophenyl)-N-[[2-(4-morpholinyl)-3-pyridinyl]methyl]-3-pyridinecarboxamide A887826; 200 nM
  • TTX-sensitive Na v l.l 1.2, 1.3, 1.4, 1.6, 1.7 channels and TTX-resistant Na v 1.8, respectively.
  • VDCC currents were evoked by a 0 mV step depolarization (200 ms) once every 30 s to minimize Ca 2+ current run down.
  • the current-to-voltage relationship (I-V plot) of Ca 2+ currents was obtained by eliciting 10 depolarizing voltage steps (200 ms duration, 10 mV increments, 5 s interval) from -50 to +50 mV starting from a holding potential (Vh) of -65 mV.
  • Example 10 A3AR agonists reduce colitis-induced visceral hypersensitivity in rats
  • VMR and AWR viscero-motor and the abdominal withdrawal responses (VMR and AWR) to the progressive increase in colorectal distension (CRD) were measured using increasing filling volumes (highest volume: 3 ml, to avoid tissue damage).
  • VMR viscero-motor and the abdominal withdrawal responses (VMR and AWR) to the progressive increase in colorectal distension (CRD) were measured using increasing filling volumes (highest volume: 3 ml, to avoid tissue damage).
  • VMR was significantly higher in comparison to controls (vehicle + vehicle; FIGs. 1A and 1C) starting from 2 ml whereas AWR was already altered by 1 ml (FIGs. IB and ID).
  • the effects of the acute i.p. administration of MRS5980 (0.3, 1.2, 2.4 pmol kg 1 ) were evaluated (FIGs. 1A-D).
  • MRS5980 dose-dependently reduced the post- inflammatory visceral hypersensitivity induced by DNBS; the magnitude of the reduction was similar for VMR and AWR.
  • the highest dose (2.4 pmol kg 1 ) completely reversed the sensitivity alteration back to the value of control rats.
  • MRS5980 1.2 pmol kg 1 partially, but significantly reduced the response of the animals to CRD.
  • the lowest dose of MRS5980 (0.3 pmol kg 1 ) was ineffective in both tests (FIGs. 1A and IB).
  • the effect of MRS5980 (0.3, 1.2, 2.4 miho ⁇ kg 1 ) was confirmed (VMR and AWR to CRD, FIGs. 1C and ID, respectively).
  • FIG. 2A shows the result of the pre-treatment with the selective A3AR antagonist MRS1523 on the anti-hyperalgesic effect of MRS5980 on day 14.
  • MRS1523 (5 pmol kg 1 ) completely abolished the pain-relieving effect of MRS5980 (2.4 pmol kg 1 ) confirming a A3AR mechanism of action.
  • the pain-relieving effect evoked by A3AR stimulation was confirmed by using another selective A3AR agonist, Cl-IB-MECA.
  • Cl-IB-MECA another selective A3AR agonist
  • FIG. 2A-D tests were performed 14 days after DNBS treatment by measuring the viscero-motor response (VMR) to colo-rectal distension (CRD) after compound administration.
  • VMR viscero-motor response
  • CCD colo-rectal distension
  • FIG. 2A Effect of pre-treatment with the selective A3 antagonist MRS 1523 (5 pmol kg 1 ) on the visceral pain-relieving effect of the highly-selective A3AR agonist, MRS5980 (5 pmol kg 1 ).
  • FIG. 2B Effect of the selective A3 agonist, Cl-IB-MECA (0.03, 0.3, and 2.4 pmol kg 1 ; i.p.).
  • A3AR agonists may inhibit Ca v 2.2-mediated currents in DRG neurons. In some cases, this may suggest a possible mechanism for pain relief.
  • the effect of acute administration of the selective N-type Ca v 2.2 blocker PD173212 may be evaluated in the visceral pain model.
  • the test (VMR assessment) was performed on day 14 after DNBS injection. As shown in FIG. 3C, PD173212 (0.0017 - 1.7 pmol kg 1 , i.p.) dose-dependently reduced the visceral hypersensitivity induced by DNBS. The compound’s effect was first apparent at a dose of 0.017 pmol kg 1 and completely relieved abdominal pain when administered at a ten-fold higher dose (FIG. 2C).
  • Example 12 Effect of the clinically-used drug linaclotide in the DNBS model
  • Example 13 MRS5980 reduces persistent visceral pain
  • this type of pain may have the peculiar tendency to become chronic in patients remitting from an intestinal damage.
  • the assessment of AWR may allow the evaluation of DNBS-induced hypersensitivity for a long time permitting the measurement of persistent pain.
  • the behavioural response was still altered 28 and 35 days after the colonic irritation (FIGs 3A and 3B, respectively).
  • this test was used to evaluate the effect of MRS5980 on visceral pain in a more delayed phase after the initial insult.
  • the pain-relieving effect of MRS5980 (0.3, 1.2, 2.4 pmol kg 1 ) was as potent as that seen earlier.
  • the effect on chronic hypersensitivity was dose-dependent and the highest dose (2.4 pmol kg 1 ) was again able to reverse the pain threshold of DNBS-treated animals to the value of controls (FIGs. 3A and 3B).
  • 70 kDa FITC was detected in vehicle treated samples in segments 5 (8.9 ⁇ 2.5 pg/ml), 6 (3.0 ⁇ 2.2.2 pg/ml) and 8 (6.3 ⁇ 3.2 pg/ml).
  • MRS5980 treatment showed a similar pattern of GI transit of 70kDa FITC; segment 5: 11.17 ⁇ 5.0 pg/ml, segment 6: 11.2 ⁇ 6.3 pg/mL, and segment 8: 15.1 ⁇ 14.3 pg/ml.
  • Detection of 70 kDa FITC-dextran in all other segments was ⁇ 4pg/ml (2.1-3.7pg/ml).
  • FIG. 4A-B Amount of 70 kDA FITC-dextran in segments of the small intestine 15 min after MRS5980 or vehicle dosing and 40 min after oral gavage of the marker.
  • Cl-IB-MECA (30 nM) may inhibit PD173232-sensitive N-type Ca 2+ currents in DRG neurons isolated either from control or DNBS-treated rats (FIGs. 6A, B) and the effect was blocked by the A3AR antagonist, MRS1523 (100 nM: FIG. 6B).
  • MRS1523 100 nM: FIG. 6B
  • MRS5980 (30 nM): the compound inhibited, to a similar extent, Ca 2+ currents either in control or DNBS neurons and the effect was prevented by MRS 1523 and by the N-type channel blocker, PD 173232 (1 mM: FIGs. 6C-E).
  • FIG. 6A Time course (left panel) and representative Ca 2+ current traces (right panel) measured in a representative DRG neuron isolated from a DNBS- treated rat (DNBS) before and after the application of the A3R agonist Cl-IB-MECA (Cl- IBM: 30 nM) or the Ca 2+ channel blocker Cd 2+ (100 mM).
  • FIG. 6B Averaged time courses of peak Ca 2+ currents during Cl-IB-MECA (30 nM) superfusion in control (vehicle) or DNBS animals in the absence or presence of the A3AR antagonist, MRS1523 (1523: 100 nM).
  • Example 16 A3AR agonists reduce colitis-induced visceral hypersensitivity in rats
  • FIG. 7 A rat model of IBS was created via rectal instillation of the mucosal sensitizing agent, dinitrobenzene sulfonic acid (DNBS; 30 mg in 0.25 mL EtOH 50%). Changes in the pain threshold are assessed by measuring the abdominal viscero-motor reflex evoked by colo-rectal distension following inflation of a balloon placed in the rectum. The magnitude of the reflex is assessed via electromyography recorded from the abdominal muscle and expressed as the signal integral immediately before the distension (30 s) subtracted from the integral during distension (30 s), expressed as percentage increase from the baseline.
  • DNBS dinitrobenzene sulfonic acid

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Abstract

L'invention concerne des méthodes et des compositions de traitement du syndrome du côlon irritable par administration au patient le nécessitant d'un agoniste sélectif de l'A3AR. En particulier, l'invention concerne des méthodes et des compositions utilisables pour traiter la douleur et l'inconfort associés au syndrome du côlon irritable par administration au patient le nécessitant d'un agoniste sélectif de l'A3AR.
PCT/US2019/062294 2018-11-19 2019-11-19 Traitement du syndrome du côlon irritable Ceased WO2020106773A1 (fr)

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US8518957B2 (en) * 2009-12-02 2013-08-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methanocarba adenosine derivatives, pharmaceutical compositions, and method of reducing intraocular pressure
US8916570B2 (en) * 2008-03-31 2014-12-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A3 adenosine receptor agonists and antagonists
US20150087613A1 (en) * 2013-09-26 2015-03-26 Saint Louis University Inhibition of Opioid Antinociceptive Tolerance and Withdrawal in Nociceptive Pain Therapy
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WO2009010871A2 (fr) * 2007-07-13 2009-01-22 Addex Pharma S.A. Nouveaux dérivés hétéroaryle servant d'antagonistes du récepteur a3 de l'adénosine
US8916570B2 (en) * 2008-03-31 2014-12-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services A3 adenosine receptor agonists and antagonists
US8518957B2 (en) * 2009-12-02 2013-08-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methanocarba adenosine derivatives, pharmaceutical compositions, and method of reducing intraocular pressure
US20150087613A1 (en) * 2013-09-26 2015-03-26 Saint Louis University Inhibition of Opioid Antinociceptive Tolerance and Withdrawal in Nociceptive Pain Therapy
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EP4196219A1 (fr) * 2020-08-17 2023-06-21 Biointervene, Inc. Analogues du récepteur a3 de l'adénosine pour le traitement d'une maladie

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