Exendin agonist compounds

• US 7,696,161 B2
• Filed: 05/25/2007
• Issued: 04/13/2010
• Est. Priority Date: 11/14/1997
• Status: Expired due to Fees

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Prickett, Kathryn S., Beeley, Nigel Robert Arnold
• Primary Examiner(s): Desai; Anand U
• Assistant Examiner(s): LIU, SAMUEL W
• Application Number:
  US11/807,031
• Publication Number:
  US 20080119393A1
• Time in Patent Office: 1,054 Days
• Field of Search: None
• US Class Current: 514/6.5
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides

Abstract

Novel exendin agonist compounds are provided. These compounds are useful in treating diabetes and conditions which would be benefited by lowering plasma glucose or delaying and/or slowing gastric emptying.

Claims

1. A compound consists of

2. The compound according to claim 1 wherein X_aa1 is His or Tyr.

3. The compound according to claim 2 wherein X_aa1 is His.

4. The compound according to claim 2 wherein X_aa2 is Gly.

5. The compound according to claim 4 wherein X_aa14 is Leu, pentylglycine or Met.

6. The compound according to claim 5 wherein X_aa25 is Trp or Phe.

7. The compound according to claim 6 wherein X_aa6 is Phe or naphthylalanine;

and X_aa22 is Phe or naphthylalanine;

X_aa23 is Ile or Val.

8. The compound according to claim 7 wherein Z₁ is —

NH₂.

9. The compound according to claim 7 wherein X_aa31, X_aa36, X_aa37 and X_aa38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine.

10. The compound according to claim 9 wherein Z₂ is —

NH₂.

11. The compound according to claim 1 wherein X_aa2 is Gly.

12. The compound according to claim 1 wherein X_aa14 is Leu, pentylglycine or Met.

13. The compound according to claim 1 wherein X_aa25 is Trp or Phe.

14. The compound according to claim 1 wherein X_aa6 is Phe or naphthylalanine;

X_aa22 is Phe or naphthylalanine;

Xaa23 is Ile or Val.

15. The compound according to claim 1 wherein Z₁ is —

NH₂.

16. The compound according to claim 1 wherein X_aa31, X_aa36, X_aa37 and X_aa38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine.

17. The compound according to claim 1 wherein Z₂ is —

NH₂.

18. The compound according to claim 1 which has an amino acid sequence selected from SEQ ID NOs:

5 to 65.

19. A method for the treatment of diabetes mellitus comprising the administration of a therapeutically effective amount of a compound according to claim 18.

20. The method of claim 19 further comprising the administration of a therapeutically effective amount of an insulin.

21. The method for the treatment of a hyperglycemic condition in a mammal comprising the step of administering a therapeutically effective amount of a compound according to claim 18.

22. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

23. A method for the treatment of diabetes mellitus comprising the administration of a therapeutically effective amount of a compound according to claim 1.

24. The method of claim 23 further comprising the administration of a therapeutically effective amount of an insulin.

25. The method for the treatment of a hyperglycemic condition in a mammal comprising the step of administering a therapeutically effective amount of a compound according to claim 1.

26. A compound consists of

27. The compound according to claim 26 which has an amino acid sequences selected from SEQ ID NOs:

7-19.

28. A method for the treatment of diabetes mellitus comprising the administration of a therapeutically effective amount of a compound according to claim 27.

29. The method of claim 28 further comprising the administration of a therapeutically effective amount of an insulin.

30. A composition comprising the compound of claim 26 and a pharmaceutically acceptable carrier.

31. A method for the treatment of diabetes mellitus comprising the administration of a therapeutically effective amount of a compound according to claim 26.

32. The method of claim 31 further comprising the administration of a therapeutically effective amount of an insulin.

33. A compound consists of

34. The compound according to claim 33 wherein X_aa1 is His, Tyr, or 4-imidazopropionyl.

35. The compound according to claim 34 wherein X_aa1 is His.

36. The compound according to claim 34 wherein X_aa1 is 4-imidazopropionyl.

37. The compound according to claim 33 wherein X_aa2 is Gly.

38. The compound according to claim 33 wherein X_aa14 is Leu, pentylglycine, or Met.

39. The compound according to claim 33 wherein X_aa25 is Trp or Phe.

40. The compound according to claim 33 wherein X_aa6 is Phe or naphthylalanine;

X_aa22 is Phe or naphthylalanine; and

X_aa23 is Ile or Val.

41. The compound according to claim 33 wherein Z₁ is —

NH₂.

42. The compound according to claim 33 wherein X_aa31, X_aa36, X_aa37 and X_aa38 are independently selected from the group consisting of Pro, homoproline, thioproline, and N-alkylalanine.

43. The compound according to claim 33 wherein Z₂—

NH₂.

44. The A compound according to claim 33 wherein X₁ is Lys Asn, Lys-NH^ε

—

R Asn, or Lys-NH^ε

—

R Ala wherein R is Lys, Arg, C₁-C₁₀ straight chain or branched alkanoyl.

45. The compound according to claim 33 wherein X_aa21 is Lys-NH^ε

—

R where R is Lys, Arg, C₁-C₁₀ straight chain or branched alkanoyl or cycloalkylkanoyl.

46. A composition comprising the compound of claim 33 and a pharmaceutically acceptable carrier.

47. A compound comprising the acid sequence of SEQ ID NO:

6, 67, 68, 69, 70, 71, 72, 73, or 74.

48. A composition comprising the compound of claim 47 and a pharmaceutically acceptable carrier.