EP1496940A2 - Pde 11a inhibitoren zur behandlung von diabetes - Google Patents

Pde 11a inhibitoren zur behandlung von diabetes

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Publication number
EP1496940A2
EP1496940A2 EP03716641A EP03716641A EP1496940A2 EP 1496940 A2 EP1496940 A2 EP 1496940A2 EP 03716641 A EP03716641 A EP 03716641A EP 03716641 A EP03716641 A EP 03716641A EP 1496940 A2 EP1496940 A2 EP 1496940A2
Authority
EP
European Patent Office
Prior art keywords
inhibitor
pdel
diabetes
insulin
administering
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03716641A
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English (en)
French (fr)
Inventor
Haren Vasavada
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharmaceuticals Corp
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Bayer Pharmaceuticals Corp
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Filing date
Publication date
Application filed by Bayer Pharmaceuticals Corp filed Critical Bayer Pharmaceuticals Corp
Publication of EP1496940A2 publication Critical patent/EP1496940A2/de
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to methods of treating diabetes and related disorders by administering a compound that inhibits PDE11 A.
  • Type 1 diabetes or insulin dependent diabetes mellitus (IDDM) arises when patients lack insulin-producing beta-cells in their pancreatic glands.
  • IDDM insulin dependent diabetes mellitus
  • Type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM)
  • IIDDM insulin dependent diabetes mellitus
  • the current treatment for type 1 diabetic patients is the injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin.
  • the drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, metformin and insulin.
  • Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose.
  • the drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.
  • cAMP cyclic adenosine monophosphate
  • Endogenous secretagogues use the cAMP system to regulate insulin secretion in a glucose-dependent fashion ( Komatsu, M., et al., Diabetes 46: 1928-1938, (1997)).
  • Examples of such endogenous secretagogues include pituitary adenylate cyclase activating peptide (PACAP), vasoactive intestinal polypeptide (NIP), and glucagon-like peptide-1 (GLP-1)
  • PACAP is a potent stimulator of glucose-dependent insulin secretion from pancreatic beta cells.
  • Three different PACAP receptor types (RI, R2, and R3) have been described (Harmar, A. et al., Pharmacol. Reviews 50: 265-270 (1998)).
  • the insulinotropic action of PACAP is mediated by the GTP binding protein Gs. Accumulation of intracellular cAMP in turn activates nonselective cation channels in beta cells increasing [Ca "1""1" ], and promoting the exocytosis of insulin-containing secretory granules.
  • Vasoactive intestinal peptide is a 28 amino acid peptide that was first isolated from hog upper small intestine (Said and Mutt, Science 169: 1217-1218, 1970; U.S. Patent No. 3,879,371). The biological effects of VIP are mediated by the activation of membrane- bound receptor proteins that are coupled to the intracellular cAMP signaling system.
  • GLP-1 is released from the intestinal L-cell after a meal and functions as an incretin hormone (i.e., it potentiates glucose-induced insulin release from the pancreatic beta cell). It is a 37-amino acid peptide that is differentially expressed by the glucagon gene, depending upon tissue type. The clinical data that support the beneficial effect of raising cAMP levels in ⁇ -cells have been collected with GLP-1. Infusions of GLP-1 in poorly controlled type 2 diabetics normalized their fasting blood glucose levels (Gutniak, M., et al., New Eng. J. Med.
  • endogenous secretagogues to treat type 2 diabetes also has some drawbacks. For instance, the peptidyl nature of these compounds requires that they be administered by injection. Additionally, the effects of the endogenous secretagogues are short-lived because of the short half-life of the peptides.
  • new therapies to treat type 2 diabetes are needed.
  • new treatments to retain normal (glucose-dependent) insulin secretion are needed.
  • Such new drugs should have the following characteristics: 1) dependency on glucose for promoting insulin secretion, i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose and therefore low probability for hypoglycemia; 2) low primary and secondary failure rates; and 3) preservation of islet cell function.
  • the present invention addresses these needs by focussing on regulation of the cAMP signaling system by inhibition of Phosphodiesterase 11 A (PDE11 A).
  • Phosphodiesterases are a family of cAMP and/or cGMP-hydrolyzing enzymes that cleave 3',5'-cyclic nucleotide monophosphates to 5'-nucleotide monophosphates. PDEs are known to be involved in the regulation of the cAMP system.
  • PDE11A is a phosphodiesterase that hydro lyses cAMP and cGMP with K m values of approximately 1-5 ⁇ M (Fawcett, et al, Proc Natl Acad Sci U S A, 2000 Mar 28;97(7):3702-7 (2000); Hetman, et al, Proc Natl Acad Sci U S A, 2000 Nov 7;97(23):12891-5 (2000); Yuasa, et al, Eur J Biochem, 2001 Aug;268(16):4440-8 (2001)).
  • the present invention relates to methods of treating diabetes, particularly type 2 diabetes, in a mammal by administering an effective amount of a PDE11 A inhibitor.
  • Other methods of the invention relate to treatment of other disorders related to diabetes, such as Syndrome X, impaired glucose tolerance and impaired fasting glucose, by administering a PDE11 A inhibitor.
  • the invention further relates to methods of stimulating insulin release from pancreatic cells in a mammal by administering an effective amount of a PDE11 A inhibitor. This method of insulin release may be in response to an elevation of the concentration of glucose in the blood of a mammal.
  • the PDE11 A inhibitor may also be administered in conjunction with other diabetes therapies, such as alpha- glucosidase inhibitors (e.g., acarbose), insulin sensitizers (e.g., thiazolidinediones), compounds that reduce hepatic glucose output (e.g., metformin), insulin secretagogues (e.g., sulfonylureas), beta3-agonists, and insulin.
  • the PDE11 A inhibitor may be administered in conjunction with one or more weight reduction agents, such as Xenical, Meridia, a beta3 -agonist or a CB-1 antagonist.
  • methods of the invention provide for the administration of a PDE11 A inhibitor in combination with an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, or an antihypertensive drug.
  • a PDE11 A inhibitor may be administered for the treatment of dementia or a urogenital tract disorder.
  • Urogenital tract disorders include, but are not limited to, incontinence, stress incontinence, benign prostatic hyperplasia, erectile dysfunction, female sexual dysfunction, and hypertrophy of prostate.
  • a PDE11 A inhibitor may be administered for the treatment of a cardiovascular disorder, such as hypertension, ischemic heart disease, myocardial infarction, stable and unstable angina, peripheral occlusive disease, and ischemic stroke.
  • the present invention therefore provides methods for the treatment of diabetes by inhibition of PDE11 A through the administration of a PDE11A inhibitor.
  • Figures 1A-1C show the expression of PDEl 1 A in islet cells.
  • Figure 1 A shows the PCR product generated from islet cDNA as template using the
  • Figure IB shows the PCR product generated from islet cDNA using the For3/R2 primer combination.
  • Figure 1C shows the PCR product generated from islet cDNA using the F4/Rev2 primer combination.
  • Methods of the invention provide for the treatment of diabetes and related disorders, particularly type 2 diabetes, and/or stimulation of insulin release from pancreatic cells, by the administration of a PDEl 1 A inhibitor.
  • Such methods provide for treatment of any condition in which glucose is elevated in the fasting or post-prandial state, by administration of a PDEl 1 A inhibitor.
  • PDEl 1 A has been identified in islets of Langerhans.
  • PDEl 1 A hydrolyses cAMP to AMP and thereby decreases intracellular concentrations of cAMP.
  • intracellular levels of cAMP are increased thereby increasing the release of insulin-containing secretory granules and therefore increasing insulin secretion.
  • a PDEl 1 A inhibitor may be administered for the treatment of dementia, a cardiovascular disease or a urogenital tract disorder.
  • Methods of the invention may be used to treat diseases, such as diabetes, including both Type 1 and Type 2 diabetes. Such methods may also delay the onset of diabetes and diabetic complications.
  • Other diseases and conditions that may be treated or prevented using methods of the invention include: Maturity-Onset Diabetes of the Young (MODY) (Herman, et al, Diabetes 43:40 (1994)), Latent Autoimmune Diabetes Adult (LAD A) (Zimmet, et al, Diabetes Med. 11 :299 (1994)), impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1) S5 (1999)), impaired fasting glucose (IFG) (Charles, et al, Diabetes 40:796 (1991)), gestational diabetes (Metzger, Diabetes, 40:197 (1991), and metabolic syndrome X.
  • MODY Maturity-Onset Diabetes of the Young
  • LAD A Latent Autoimmune Diabetes Adult
  • ITT impaired glucose tolerance
  • IGF impaired fasting glucose
  • Methods of the invention may also be used to treat secondary causes of diabetes (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1), S5 (1999)).
  • secondary causes include glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes.
  • Drugs that may induce diabetes include, but are not limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin, thyroid hormone, ⁇ - adrenergic agents, ⁇ -interferon and drugs used to treat HIN infection.
  • cAMP-mediated release of insulin is also dependent on the presence of stimulatory glucose concentrations.
  • a method of the invention further relates to stimulating insulin release from islet cells by the administration of a PDEl 1 A inhibitor. Glucose-dependent stimulation of insulin secretion with non-peptide compounds therefore lowers blood glucose concentrations without causing hypoglycemia.
  • a PDEl 1 A inhibitor may be used partially or completely, in combination therapy.
  • a PDEl 1 A inhibitor may also be administered in combination with other known therapies for the treatment of diabetes, including PPAR agonists, sulfonylurea drugs, non- sulfonylurea secretagogues, -glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, and insulin.
  • Such therapies may be administered prior to, concurrently with or following administration of the PDEl 1 A inhibitor.
  • Insulin includes both long and short acting forms and formulations of insulin.
  • PPAR agonist may include agonists of any of the PPAR subunits or combinations thereof.
  • PPAR agonist may include agonists of PPAR- ⁇ , PPAR- ⁇ , PPAR- ⁇ or any combination of two or three of the subunits of PPAR.
  • PPAR agonists include, for example, rosiglitazone and pioglitazone.
  • Sulfonylurea drugs include, for example, glyburide, glimepiride, chlorpropamide, and glipizide.
  • ⁇ -glucosidase inhibitors that may be useful in treating diabetes when administered with a PDEl 1 A inhibitor include acarbose, miglitol and voglibose.
  • Insulin sensitizers that may be useful in treating diabetes when administered with a PDEl 1 A inhibitor include thiazolidinediones and non-thiazolidinediones.
  • Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a PDEl 1 A inhibitor include metformin, such as Glucophage and Glucophage XR.
  • Insulin secretagogues that may be useful in treating diabetes when administered with a PDEl 1 A inhibitor include sulfonylurea and non-sulfonylurea drugs: GLP-1, GIP, PAC/VPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide.
  • GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1, such as, for example, fatty-acid derivatized GLP-1 and exendin.
  • a PDEl 1 A inhibitor is used in combination with insulin secretagogues to increase the sensitivity of pancreatic beta cells to the insulin secretagogue.
  • a PDEl 1 A inhibitor may be used in combination with anti-obesity drugs.
  • Anti- obesity drugs include ⁇ -3 agonists, CB-1 antagonists, appetite suppressants, such as, for example, sibutramine (Meridia), and lipase inhibitors, such as, for example, orlistat (Xenical).
  • a PDEl 1 A inhibitor may also be used in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such drugs include, but are not limited to, HMG- CoA reductase inhibitors, nicotinic acid, bile acid sequestrants, and fibric acid derivatives. Methods of the invention may also be used in combination with anti-hypertensive drugs, such as, for example, ⁇ -blockers and ACE inhibitors.
  • Such co-therapies may be administered in any combination of two or more drugs (e.g., a PDEl 1 A inhibitor in combination with an insulin sensitizer and an anti-obesity drug).
  • Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
  • PDEl 1 A inhibitor for the treatment of dementia. Shimamoto, et al, Mechanisms of Aging Development (1976), 5 (4): 241-250; Nicholson, et al, Trends Pharmacological Sciences (1991), 12 (1): 19-27.
  • Still further methods of the invention relate to treatment of urogenital tract disorders by the administration of a PDEl 1 A inhibitor.
  • urogenital tract disorders include, but are not limited to, incontinence, stress incontinence, benign prostatic hyperplasia, erectile dysfunction, female sexual dysfunction (including female sexual arousal disorder), and hypertrophy of prostate. Ballard, et al, J Urology 159 (6): 2164-2171 (1998); EP 1211313A2 (for effects of PDE 11 A on spermato genesis).
  • a PDEl 1A inhibitor to treat cardiovascular disorders, such as hypertension, ischemic heart disease, myocardial infarction, stable and unstable angina, peripheral occlusive disease, and ischemic stroke.
  • the PDEl 1 family comprises enzymes which are responsible for the degradation of cAMP and cGMP in various tissues (Fawcett, et.al, PNAS (2000) 97, 3702-3707). Furthermore, expression of PDEl 1 can be detected in the heart (Yuasa, et.al, Eur. J. Biochem. (2001) 268, 4440-4448).
  • Cyclic GMP cGMP
  • cyclic AMP cyclic AMP
  • GPCRs G protein-coupled receptors
  • PDEs 3',5'-cyclic nucleotide phosphodiesterases
  • a PDEl 1A inhibitor for use in methods of the invention may be administered as compound per se.
  • a PDEl 1 A inhibitor may be administered with an acceptable carrier in the form of a pharmaceutical composition.
  • the pharmaceutically acceptable carrier must be compatible with the other ingredients of the composition and must not be intolerably deleterious to the recipient.
  • the carrier can be a solid or a liquid, or both, and preferably is formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from about 0.05% to about 95% by weight of the active compound(s) based on a total weight of the dosage form.
  • Other pharmacologically active substances can also be present, including other compounds useful in the treatment of a diabetic condition.
  • a PDEl 1 A inhibitor for use in methods of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a therapeutically effective dose for the treatment intended.
  • the PDEl 1 A inhibitor may, for example, be administered orally, sublingually, nasally, pulmonarily, mucosally, parenterally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
  • Unit dose formulations, particularly orally administrable unit dose formulations such as tablets or capsules generally contain, for example, from about 0.001 to about 500 mg, preferably from about 0.005 mg to about 100 mg, and more preferably from about 0.01 to about 50 mg, of the active ingredient.
  • the weights indicated above for the active ingredient refer to the weight of the pharmaceutically active ion derived from the salt.
  • the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a suspension, an emulsion, a paste, a solution, a syrup or other liquid form.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • the compounds may be admixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • lactose sucrose, starch powder
  • cellulose esters of alkanoic acids cellulose alkyl esters
  • talc stearic acid
  • magnesium stearate magnesium oxide
  • sodium and calcium salts of phosphoric and sulfuric acids gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol
  • Oral delivery of a PDEl 1 A inhibitor can include formulations well known in the art to provide immediate delivery or prolonged or sustained delivery of a drug to the gastrointestinal tract by any number of mechanisms.
  • Immediate delivery formulations include, but are not limited to, oral solutions, oral suspensions, fast-dissolving tablets or capsules, sublingual tablets, disintegrating tablets and the like.
  • Prolonged or sustained delivery formulations include, but are not limited to, pH sensitive release of the active ingredient from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form.
  • enteric-coated and enteric-coated controlled release formulations may be used in methods of the present invention.
  • Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.
  • compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water- in-oil emulsion.
  • such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the inhibitors) and the carrier (which can constitute one or more accessory ingredients), h general, the compositions are prepared by uniformly and intimately admixing the inhibitor(s) with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet can be prepared by compressing or molding a powder or granules of the inhibitors, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets can be made, for example, by molding the powdered compound in a suitable machine.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • compositions suitable for buccal (sub-lingual) administration include lozenges comprising a PDEl 1 A inhibitor in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the inhibitors in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations for parenteral administration may be in the form of aqueous or non- aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • a PDEl 1 A inhibitor may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • compositions containing PDEl 1 A inhibitors for use in methods of the invention can be prepared by any of the well-known techniques of pharmacy, such as admixing the components.
  • the above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Dosage levels of the PDEl 1 A inhbitors for use in methods of this invention typically are from about 0.001 mg to about 10,000 mg daily, preferably from about 0.005 mg to about 1,000 mg daily. On the basis of mg/kg daily dose, either given in a single or divided doses, dosages typically range from about 0.001/75 mg/kg to about 10,000/75 mg/kg, preferably from about 0.005/75 mg/kg to about 1,000/75 mg/kg.
  • the total daily dose of each inhibitor can be administered to the patient in a single dose, or in multiple subdoses.
  • subdoses can be administered two to six times per day, preferably two to four times per day, and even more preferably two to three times per day.
  • Doses can be in immediate release form or sustained release form sufficiently effective to obtain the desired control over the diabetic condition.
  • the dosage regimen to prevent, treat, give relief from, or ameliorate a diabetic condition or disorder, or to otherwise protect against or treat a diabetic condition with the combinations and compositions of the present invention is selected in accordance with a variety of factors. These factors include, but are not limited to, the type, age, weight, sex, diet, and medical condition of the subject, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular inhibitors employed, whether a drug delivery system is utilized, and whether the inhibitors are administered with other active ingredients. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.
  • Pharmaceutically-acceptable salts of the compounds useful as PDEl 1 A inhibitors in methods of the present invention include salts commonly used to form alkali metal salts or form addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocychc, carboxylic and sulfonic classes of organic acids.
  • organic and sulfonic classes of organic acids includes, but are not limited to, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric, salicyclic, galactaric and galacturonic acid and combinations thereof.
  • a PDEl 1 A inhibitor for use in methods of the invention may also be administered as the pharmaceutically acceptable salt, protected acid, conjugate acid, tautomer, prodrug or stereoisomer of a compoimd found to inhibit the activity of PDEl 1 A.
  • Tautomers include, for example, hydroxy tautomers.
  • Protected acids include, but are not limited to, protected acids such as esters, hydroxyamino derivatives, amides and sulfonamides.
  • prodrugs are well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems " (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference).
  • prodrugs are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention.
  • Major drug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 11- 13, (1996), which is hereby incorporated by reference).
  • a PDEl 1 A inhibitor may also be useful for veterinary treatments of companion animals (e.g., horses, dogs, cats, etc.), exotic animals and farm animals. Even though the invention is described in terms of human biology, it is understood by those of ordinary skill in the art that the present invention is applicable to other mammals as well.
  • PDEl 1 A in pancreatic islets was verified by PCR. PCR was performed using template DNA from an islet cDNA library with the following primer combinations that recognize different regions throughout the PDEl 1 A gene:
  • 50 ⁇ l PCR reactions were assembled as follows: 5 ⁇ l lOx Amplification Buffer (supplied with polymerase)
  • the reactions were loaded on 1% agarose TBE gels and electrophoresed at 150 V for 20 min.
  • the PCR products were visualized by UV illumination after Ethidium Bromide staining.
  • DNA sequencing as this product corresponded to the portion of the PDEl 1 A gene encoding the catalytic domain. Briefly, the PCR band was excised from the gel and purified using Qiagen Gel Extraction Kit following the protocol supplied with the kit. Purified PCR product was inserted into the pcDNA3.1/N5/His-TOPO vector followed by transformation of TOP 10 competent bacterial cells using the Eukaryotic TOPO TA Cloning Kit (Invitrogen), as described by the manufacturer. Five colonies were picked into 2 ml LB broth with lOOug/ml carbenicillin and grown at 37°C overnight. Miniprep DNA was prepared from the overnight cultures the presence of PCR product insert was verified by restriction enzyme analysis. The insert was positively identified as PDEl 1 A by DNA sequencing.
  • Figures 1A-1C show the PDEl 1 A PCR products generated using the primer combinations described above. As shown in the figures, PDEl 1 A is found in islet cells. Expression of PDEl 1A in islet cells indicates that PDEl 1A may have a role in regulating insulin release/blood glucose concentrations.
  • Compound is added to human recombinant enzyme in assay buffer to a 96-well whitewall/clear bottom isoplate (Wallac).
  • the reaction is initiated by the addition of 3H- cAMP (Amersham) or 3H-cGMP (Amersham). After 45 minutes at room temperature, the reaction is stopped by the addition of SPA yttrium silicate beads (Amersham). After 30 minutes, the plate is read in the Microbeta (Wallac) for 30 seconds in the SPA mode. Data is expressed as a percentage of control.
  • PDE2 PDE3A, PDE4B, and PDEl 1A
  • 3H-cAMP was used as a substrate.
  • PDE5 3H-cGMP was used as a substrate.
  • Pancreatic islet isolation Lean rats (Sprague-Dawley, male, 200-250g) are anesthetized with nembutal (60mg/kg, i.p.) and the abdomen opened to expose the liver and pancreas. The pancreas is distended by injection of Hank's solution into the bile duct, and then the pancreas is excised and minced with scissors while in Hank's solution. After rinsing the tissue with buffer, the pancreas is digested for ten minutes with collagenase, rinsed, and the islets separated from debris on a Ficoll gradient. The isolated islet fraction is rinsed with buffer, and the islets hand-picked under a microscope.
  • the islets are pre-incubated in 3mM glucose for 30 minutes and then transferred to media containing the appropriate conditions and incubated for an additional 30 minutes.
  • the media is then assayed for insulin content using an ELIS A kit (Alpco Diagnostics, Windham, NH).
  • Lean rats (Wistar, male, 250 - 300 g) are fasted overnight and divided into two groups: Vehicle and compound treatment (8 rats per group). Vehicle or compound is administrated via oral gavage (1.5 ml/rat). Two hours later, glucose solution (30%, 2 g/kg body weight) is injected intraperitoneally. Tail blood samples are collected at 0, 15, 30, and 60 min after glucose injection to measure blood glucose using Glucometer (Bayer Diagnostics, Mishawaka, IN). Compounds identified in the PDEl 1 A inhibition assay described above and tested in the islet assay described above are anticipated to have a blood glucose lowering effect when tested in this assay.

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MEP8509A (en) 2006-09-07 2011-12-20 Combination treatment for diabetes mellitus
KR101560844B1 (ko) 2007-06-04 2015-10-15 벤-구리온 유니버시티 오브 더 네게브 리서치 앤드 디벨럽먼트 어쏘러티 트라이-아릴계 화합물 및 이를 포함하는 조성물
EP3199203B1 (de) 2008-02-29 2020-02-05 Concert Pharmaceuticals Inc. Substituierte xanthinderivate
US20110053961A1 (en) 2009-02-27 2011-03-03 Concert Pharmaceuticals, Inc. Substituted xanthine derivatives
JP2012520342A (ja) * 2009-03-16 2012-09-06 ジェンメディカ・セラピューティックス・ソシエダッド・リミターダ 代謝障害を処置するのに有用な抗炎症剤および抗酸化剤のコンジュゲート
WO2013013052A1 (en) 2011-07-19 2013-01-24 Concert Pharmaceuticals, Inc. Substituted xanthine derivatives
JP2015067538A (ja) * 2013-09-26 2015-04-13 株式会社アイエイアイ 血糖値降下剤
CN106061940A (zh) 2013-11-05 2016-10-26 本古里安大学内盖夫研究发展局 治疗糖尿病和由其引发的并发疾病的化合物
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