Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions

• US 20060287242A1
• Filed: 06/30/2005
• Published: 12/21/2006
• Est. Priority Date: 07/02/2004
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Sulsky, Richard B., Ewing, William R., Zhu, Yeheng, Lee, Ving G., Riexinger, Douglas James, Mapelli, Claudio, Martinez, Rogelio L., Haque, Tasir Shamsul
• Granted Patent: US 7,417,028 B2
• Time in Patent Office: Days
• US Class Current: 514/1.900
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1)-receptor modulators that have biological activity similar or superior to native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 receptor modulators exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration. The peptides of this invention show desirable pharmacokinetic properties and desirable potency in efficacy models of diabetes.

Claims

1. An isolated polypeptide comprising a polypeptide having a sequence of Formula I (SEQ ID NO:

1);

X_aa1—

X_aa2—

X_aa3—

X_aa4—

X_aa5—

X_aa6—

X_aa7—

X_aa8—

X_aa9—

X_aa10—

X_aa11 

 

I

wherein,

X_aa1 is a naturally or nonnaturally occurring amino acid comprising an imidazole;

wherein one or more carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;

wherein said amino acid optionally has a free amino group which is optionally substituted with alkyl, acyl, benzoyl, L-lactyl, alkyloxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, arylalkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl; and

wherein when said free amino group is not present X_aa1 is the des-amino acid of histidine in which one or more carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;

X_aa2 is a naturally or nonnaturally occurring amino acid selected from the group consisting of D-alanine, α

-amino-isobutyric acid (Aib), N-methyl-D-alanine, N-ethyl-D-alanine, 2-methyl-azetidine-2-carboxylic acid, alpha-methyl-(L)-proline, 2-methylpiperidine-2-carboxylic acid and isovaline;

X_aa3 is a naturally or nonnaturally occurring amino acid having (1) an amino acid side chain comprising a carboxylic acid or (2) an imidazole side chain, and wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;

X_aa4 is glycine;

X_aa5 is a naturally or nonnaturally occurring amino acid selected from the group consisting of (L)-threonine and (L)-norvaline; and

wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;

X_aa6 is a naturally or nonnaturally occurring amino acid having a disubstituted alpha carbon having two side chains;

wherein at least one of said two side chains has an aromatic ring and at least one of said two chains has an alkyl group; and

wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups or one or more halo groups.

X_aa7 is a naturally or nonnaturally occurring amino acid having an amino acid side chain which is substituted with a hydroxyl group; and

wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;

X_aa8 is a naturally or nonnaturally occurring amino acid selected from the group consisting of L-serine and L-histidine; and

wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;

X_aa9 is a naturally or nonnaturally occurring amino acid having an amino acid side chain comprising a carboxylic acid; and

wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;

X_aa10 is a naturally or nonnaturally occurring amino acid of Formula II;

wherein R₄ is selected from the group consisting of hydrogen, alkyl, and halo;

wherein R₃ and R₆ are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;

wherein the phenyl ring proximal to the beta-carbon of said amino acid is additionally optionally substituted with alkyl or halo; and

wherein the phenyl ring distal to the beta-carbon of said amino acid is additionally optionally substituted with halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;

X_aa11 is a naturally or nonnaturally occurring amino acid of Formula IVa;

wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH₂);

wherein R_4a is selected from the group consisting of hydrogen, alkyl, and halo;

wherein R_3a and R_6a are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;

wherein R₇ is selected from the group consisting of hydrogen, methyl, and ethyl; and

wherein X₁, X₂, X₃ and X₄ are each C or N, with the proviso that at least one of X₁, X₂, X₃ and X₄ is N;

wherein the phenyl ring proximal to the beta-carbon of said amino acid is additionally optionally substituted with alkyl or halo; and

wherein the phenyl ring distal to the beta-carbon of said amino acid is additionally optionally substituted with halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy.

2. The isolated polypeptide of claim 1, wherein X_aa3 is histidine, wherein said histidine is optionally substituted with one or more alkyl groups.

3. The isolated polypeptide of claim 1, wherein X_aa3 is L-aspartic acid or L-glutamic acid, wherein each of said L-aspartic acid or L-glutamic acid is optionally substituted with one or more alkyl groups.

4. The isolated polypeptide of claim 1, wherein X_aa6 is alpha-methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine, or alpha-methyl-2,6-difluorophenylalanine, wherein each of said alpha-methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine, or alpha-methyl-2,6-difluorophenylalanine is optionally substituted with one or more alkyl groups.

5. The isolated polypeptide of claim 1, wherein X_aa7 is L-threonine, wherein said threonine is optionally substituted with one or more alkyl groups.

6. The isolated polypeptide of claim 1, wherein X_aa9 is L-aspartic acid or L-glutamic acid, wherein each of said L-aspartic acid or L-glutamic acid is optionally substituted with one or more alkyl groups.

7. The isolated polypeptide of claim 1, wherein X_aa1 is L-histidine, said histidine having a terminal amino group which is optionally substituted with alkyl, dialkyl, acyl, benzoyl, L-lactyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, aralkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl.

8. The isolated polypeptide of claim 1, wherein X_aa1 is selected from the group consisting of L-N-methyl-His, L-α

-methyl-His, des-amino-His, 3-(1H-imidazol-4-yl)-2-methylpropanoyl, and (S)-3-(1H-imidazol-4-yl)-2-hydroxypropanoyl(L-β

-imidazolelactyl).

9. The isolated polypeptide of claim 1, wherein X_aa2 is selected from the group consisting of α

-amino-isobutyric acid (Aib), D-alanine, N-methyl-D-alanine, alpha-methyl(L)-proline, 2-methyl-azetidine-2-carboxylic acid and 2-methylpiperidine-2-carboxylic acid.

10. The isolated polypeptide of claim 1, wherein X_aa4 is glycine.

11. The isolated polypeptide of claim 1, wherein X_aa5 is selected from the group consisting of L-Thr, and L-Nva.

12. The isolated polypeptide of claim 1, wherein X_aa6 is selected from the group consisting of L-α

-Me-Phe, L-α

-Me-2-fluoro-Phe, and L-α

-Me-2,6-difluoro-Phe.

13. The isolated polypeptide of claim 1, wherein X_aa7 is L-Thr.

14. The isolated polypeptide of claim 1, wherein X_aa8 is selected from the group consisting of L-Ser, and L-His.

15. The isolated polypeptide of claim 1, wherein X_aa9 is L-Asp.

16. The isolated polypeptide of claim 1, wherein X_aa10 is selected from the group consisting of 4-phenyl-phenylalanine, 4-[(4′

-methoxy-2′

-ethyl)phenyl]phenylalanine, 4-[(4′

-ethoxy-2′

-ethyl)phenyl]phenylalanine, 4-[(4′

-methoxy-2′

-methyl)phenyl]phenylalanine, 4-[(4′

-ethoxy-2′

-methyl)phenyl]phenylalanine, 4-(2′

-ethylphenyl)phenylalanine, 4-(2′

-methylphenyl)phenylalanine, 4-[(3′

,5′

-dimethyl)phenyl]phenylalanine and 4-[(3′

,4′

-dimethoxy)phenyl]phenylalanine.

17. The isolated polypeptide of claim 1, wherein X_aa11 is selected from the group consisting of 4-phenyl-3-pyridylalanine, 4-(2′

-methylphenyl)-3-pyridylalanine, 4-(2′

-fluorophenyl)-3-pyridylalanine, 4-(2′

-chlorophenyl)-3-pyridylalanine, 4-[(3′

,5′

-dimethyl)phenyl]-3-pyridylalanine, 4-(4′

-trifluoromethylphenyl)-3-pyridylalanine, 4-(3′

-methoxyphenyl)-3-pyridylalanine, 4-(3′

-methylphenyl)-3-pyridylalanine, 4-(2′

-methylphenyl)-3,5-pyrimidylalanine, (S)-4-(2′

-Methylphenyl)-α

-Me-3-pyridylalanine and 4-(2′

-ethylphenyl)-3-pyridylalanine;

wherein the C-terminal carbonyl carbon of X_aa11 is attached to a nitrogen to form a carboxamide (NH₂); and

wherein R₇ is selected from the group consisting of hydrogen and methyl.

18. The isolated polypeptide of claim 1, wherein said polypeptide is a polypeptide of Formula VI:

19. An isolated polypeptide of claim 18, wherein:

X_aa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α

-methyl-L-Pro and α

-aminoisobutyric (Aib);

X is fluoro;

Y is hydrogen;

X_aa8 is an amino acid selected from the group consisting of L-Ser and L-His;

R₃ is ethyl;

R₆ is methoxy;

R_3a is selected from the group consisting of methyl and ethyl;

R_6a is hydrogen; and

R₇ is hydrogen.

20. The isolated polypeptide of claim 1, wherein said polypeptide is a polypeptide of Formula VII:

21. The isolated polypeptide of claim 20, wherein:

R₈ is selected from the group consisting of methyl, and

Xaa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α

-methyl-L-Pro and aminoisobutyric acid (Aib);

X is fluoro;

Y is hydrogen;

X_aa8 is an amino acid selected from the group consisting of L-Ser and L-His;

R₃ is ethyl;

R₆ is methoxy;

R_3a is selected from the group consisting of methyl and ethyl;

R_6a is hydrogen; and

R₇ is selected from the group consisting of hydrogen and methyl.

22. The isolated polypeptide of claim 1, wherein said polypeptide is a polypeptide of Formula VIII:

23. The isolated polypeptide of claim 22, wherein:

R₉ is selected from the group consisting of hydrogen and methyl;

X_aa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α

-methyl-L-Pro, and α

-aminoisobutyric acid (Aib);

X is fluoro;

Y is hydrogen;

X_aa8 is an amino acid selected from the group consisting of L-Ser and L-His;

R₃ is ethyl;

R₆ is methoxy;

R_3a is selected from the group consisting of methyl and ethyl;

R_6a is hydrogen;

R₇ is hydrogen.

24. An isolated polypeptide of claim 1, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:

25. An isolated polypeptide of claim 24, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:

26. An isolated polypeptide of claim 1, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:

27. An isolated polypeptide of claim 1, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:

28. An isolated polypeptide of claim 1, wherein said isolated polypeptide is:

29. An isolated polypeptide of claim 28, wherein said isolated polypeptide is:

30. An isolated polypeptide of claim 1, wherein said isolated polypeptide is:

33. A pharmaceutical composition, comprising an isolated polypeptide of claim 1 and a pharmaceutically acceptable carrier thereof.

34. A pharmaceutical composition comprising an isolated polypeptide of claim 1 and at least one therapeutic agent;

wherein said therapeutic agent is selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.

35. A pharmaceutical composition of claim 34 wherein said antidiabetic agent is selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a PPAR α

/γ

dual agonist, an aP2 inhibitor, a DPP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) analog, insulin and a meglitinide.

36. A pharmaceutical composition of claim 34 wherein said antidiabetic agent is selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, muraglitazar, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, NVP-DPP-728A and saxagliptin.

37. A pharmaceutical composition of claim 34, wherein said anti-obesity agent is selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, a CB-1 antagonist, a NPY-Y2 and a NPY-Y4 receptor agonist and an anorectic agent.

38. A pharmaceutical composition of claim 34, wherein said anti-obesity agent is selected from the group consisting of orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine rimonabant (SR141716A), and mazindol.

39. A pharmaceutical composition of claim 34, wherein said lipid lowering agent is selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, and an ACAT inhibitor.

40. A pharmaceutical composition of claim 34, wherein said lipid lowering agent is selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, CP-529414, and LY295427.

41. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of an isolated polypeptide of claim 1.

42. A method of claim 41, further comprising the concurrent or sequential administration of a therapeutically effective amount of one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, and an anti-atherosclerotic agent and a lipid-lowering agent.

43. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a pharmaceutical composition of claim 34.

44. A method for administering a polypeptide of claim 1, comprising the parenteral administration of a formulation comprising a polypeptide of claim 1.

45. A method for administering a polypeptide of claim 1, comprising the non-parenteral administration of a formulation comprising a polypeptide of claim 1.

46. A method of claim 44, wherein said parenteral administration is selected from the group consisting of intravenous (IV) bolus injection, IV infusion, subcutaneous administration, intramuscular administration, intranasal administration, buccal administration, pulmonary administration and ophthalmic delivery.

47. A method of claim 46, wherein said subcutaneous administration involves the use of an immediate or sustained release formulation.

48. A method of claim 46, wherein said intramuscular administration involves the use of an immediate or sustained release formulation.

49. A method of claim 44, wherein said formulation further comprises a pharmaceutically acceptable excipient selected from the group consisting of a solvent and co-solvent, a solubilizing agent, an emulsifying agent, a thickening agent, a chelating agent, an anti-oxidant, a reducing agent, an antimicrobial preservative, a buffer and pH adjusting agent, a bulking agent, a protectant and tonicity adjustor, and a special additive.

50. A method of claim 44, wherein said formulation further comprises an encapsulated delivery system.

31. A compound of Formula VIa:

32. A compound of Formula VIIa:

51. An isolated polypeptide, wherein said polypeptide is a polypeptide of Formula VI:

52. An isolated polypeptide of claim 51, wherein:

X_aa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α

-methyl-L-Pro and α

-aminoisobutyric (Aib);

X is fluoro;

Y is hydrogen;

X_aa8 is an amino acid selected from the group consisting of L-Ser and L-His;

R₃ is ethyl;

R₆ is methoxy;

R_3a is selected from the group consisting of methyl and ethyl;

R_6a is hydrogen;

R₇ is hydrogen.

53. An isolated polypeptide, wherein said polypeptide is a polypeptide of Formula VII:

54. The isolated polypeptide of claim 53, wherein:

R₈ is selected from the group consisting of methyl,

X_aa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α

-methyl-L-Pro and aminoisobutyric acid (Aib);

X is fluoro;

Y is hydrogen;

X_aa8 is an amino acid selected from the group consisting of L-Ser and L-His;

R₃ is ethyl;

R₆ is methoxy;

R_3a is selected from the group consisting of methyl and ethyl;

R_6a is hydrogen;

R₇ is selected from the group consisting of hydrogen and methyl.

55. An isolated polypeptide, wherein said polypeptide is a polypeptide of Formula VIII:

56. The isolated polypeptide of claim 55, wherein:

R₉ is selected from the group consisting of hydrogen and methyl;

X_aa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α

-methyl-L-Pro, and α

-aminoisobutyric acid (Aib);

X is fluoro;

Y is hydrogen;

X_aa8 is an amino acid selected from the group consisting of L-Ser and L-His;

R₃ is ethyl;

R₆ is methoxy;

R_3a is selected from the group consisting of methyl and ethyl;

R_6a is hydrogen;

R₇ is hydrogen.

57. An isolated polypeptide, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:

58. An isolated polypeptide, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:

59. An isolated polypeptide, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:

60. An isolated polypeptide, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:

61. An isolated polypeptide, wherein said isolated polypeptide is:

62. An isolated polypeptide, wherein said isolated polypeptide is:

63. An isolated polypeptide, wherein said isolated polypeptide is:

64. An isolated polypeptide, wherein said isolated polypeptide is:

65. An isolated polypeptide, wherein said isolated polypeptide is:

66. An isolated polypeptide, wherein said isolated polypeptide is: