Details for Patent: 7,696,161

Title:	Exendin agonist compounds
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.
Inventor(s):	Beeley; Nigel Robert Arnold (San Diego, CA), Prickett; Kathryn S. (Hillsborough, CA)
Assignee:	Amylin Pharmaceuticals, Inc. (San Diego, CA)
Filing Date:	May 25, 2007
Application Number:	11/807,031
Claims:	1. A compound consists of TABLE-US-00077 Xaa.sub.1 Xaa.sub.2 Xaa.sub.3 Gly Xaa.sub.5 Xaa.sub.6 Xaa.sub.7 Xaa.sub.8 Xaa.sub.9 Xaa.sub.10 Xaa.sub.11 Xaa.sub.12 Xaa.sub.13 Xaa.sub.14 Xaa.sub.15 Xaa.sub.16 Xaa.sub.17 Ala Xaa.sub.19 Xaa.sub.20 Xaa.sub.21 Xaa.sub.22 Xaa.sub.23 Xaa.sub.24 Xaa.sub.25 Xaa.sub.26 Xaa.sub.27 Xaa.sub.28-Z.sub.1; wherein Xaa.sub.1 is His, Arg or Tyr; Xaa.sub.2 is Ser, Gly, Ala or Thr; Xaa.sub.3 is Asp or Glu; Xaa.sub.5 is Ala or Thr; Xaa.sub.6 is Ala, Phe, Tyr or naphthylalanine; Xaa.sub.7 is Thr or Ser; Xaa.sub.8 is Ala, Ser or Thr; Xaa.sub.9 is Asp or Glu; Xaa.sub.10 is Ala, Leu, Ile, Val, pentylglycine or Met; Xaa.sub.11 is Ala or Ser; Xaa.sub.12 is Ala or Lys; Xaa.sub.13 is Ala or Gln; Xaa.sub.14 is Ala, Leu, Ile, pentylglycine, Val or Met; Xaa.sub.15 is Ala or Glu; Xaa.sub.16 is Ala or Glu; Xaa.sub.17 is Ala or Glu; Xaa.sub.19 is Ala or Val; Xaa.sub.20 is Ala or Arg; Xaa.sub.21 is Ala or Leu; Xaa.sub.22 is Phe, Tyr or naphthylalanine; Xaa.sub.23 is Ile, Val, Leu, pentylglycine, tert- butylglycine or Met; Xaa.sub.24 is Ala, Glu or Asp; Xaa.sub.25 is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa.sub.26 is Ala or Leu; Xaa.sub.27 is Ala or Lys; Xaa.sub.28 is Ala or Asn; Z.sub.1 is --OH, TABLE-US-00078 --NH.sub.2, Gly -Z.sub.2, Gly Gly -Z.sub.2 Gly Gly Xaa.sub.31-Z.sub.2, Gly Gly Xaa.sub.31 Ser-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36 Xaa.sub.37-Z.sub.2 or Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36 Xaa.sub.37 Xaa.sub.38- Z.sub.2; wherein Xaa.sub.31, Xaa.sub.36, Xaa.sub.37 and Xaa.sub.38 are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine; and Z.sub.2 is --OH or --NH.sub.2; provided that no more than three of X.sub.aa3, X.sub.aa5, X.sub.aa6, X.sub.aa8, X.sub.aa10, X.sub.aa11, X.sub.aa12, X.sub.aa13, X.sub.aa14, X.sub.aa15, X.sub.aa16, X.sub.aa17, X.sub.aa19, X.sub.aa20, X.sub.aa21, X.sub.aa24, X.sub.aa25, X.sub.aa26, X.sub.aa27, and X.sub.aa28 are Ala; and a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1 wherein X.sub.aa1 is His or Tyr. 3. The compound according to claim 2 wherein X.sub.aa1 is His. 4. The compound according to claim 2 wherein X.sub.aa2 is Gly. 5. The compound according to claim 4 wherein X.sub.aa14 is Leu, pentylglycine or Met. 6. The compound according to claim 5 wherein X.sub.aa25 is Trp or Phe. 7. The compound according to claim 6 wherein X.sub.aa6 is Phe or naphthylalanine; and X.sub.aa22 is Phe or naphthylalanine; X.sub.aa23 is Ile or Val. 8. The compound according to claim 7 wherein Z.sub.1 is --NH.sub.2. 9. The compound according to claim 7 wherein X.sub.aa31, X.sub.aa36, X.sub.aa37 and X.sub.aa38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine. 10. The compound according to claim 9 wherein Z.sub.2 is --NH.sub.2. 11. The compound according to claim 1 wherein X.sub.aa2 is Gly. 12. The compound according to claim 1 wherein X.sub.aa14 is Leu, pentylglycine or Met. 13. The compound according to claim 1 wherein X.sub.aa25 is Trp or Phe. 14. The compound according to claim 1 wherein X.sub.aa6 is Phe or naphthylalanine; X.sub.aa22 is Phe or naphthylalanine; Xaa23 is Ile or Val. 15. The compound according to claim 1 wherein Z.sub.1 is --NH.sub.2. 16. The compound according to claim 1 wherein X.sub.aa31, X.sub.aa36, X.sub.aa37 and X.sub.aa38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine. 17. The compound according to claim 1 wherein Z.sub.2 is --NH.sub.2. 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 TABLE-US-00079 Xaa.sub.1 Xaa.sub.2 Xaa.sub.3 Gly Xaa.sub.5 Xaa.sub.6 Xaa.sub.7 Xaa.sub.8 Xaa.sub.9 Xaa.sub.10 Xaa.sub.11 Xaa.sub.12 Xaa.sub.13 Xaa.sub.14 Xaa.sub.15 Xaa.sub.16 Xaa.sub.17 Ala Xaa.sub.19 Xaa.sub.20 Xaa.sub.21 Xaa.sub.22 Xaa.sub.23 Xaa.sub.24 Xaa.sub.25 Xaa.sub.26 Xaa.sub.27 Xaa.sub.28-Z.sub.1; Wherein Xaa.sub.1 is His or Arg; Xaa.sub.2 is Gly or Ala; Xaa.sub.3 is Asp or Glu; Xaa.sub.5 is Ala or Thr; Xaa.sub.6 is Ala, Phe, Tyr or naphthylalanine; Xaa.sub.7 is Thr or Ser; Xaa.sub.8 is Ala, Ser or Thr; Xaa.sub.9 is Asp or Glu; Xaa.sub.10 is Ala, Leu or pentylglycine; Xaa.sub.11 is Ala or Ser; Xaa.sub.12 is Ala or Lys; Xaa.sub.13 is Ala or Gln; Xaa.sub.14 is Ala, Leu, or pentylglycine; Xaa.sub.15 is Ala or Glu; Xaa.sub.16 is Ala or Glu; Xaa.sub.17 is Ala or Glu; Xaa.sub.19 is Ala or Val; Xaa.sub.20 is Ala or Arg; Xaa.sub.21 is Ala or Leu; Xaa.sub.22 is Phe or naphthylalanine; Xaa.sub.23 is Ile, Val or tert-butyl glycine; Xaa.sub.24 is Ala, Glu or Asp; Xaa.sub.25 is Ala, Trp or Phe; Xaa.sub.26 is Ala or Leu; Xaa.sub.27 is Ala or Lys; Xaa.sub.28 is Ala or Asn; Z.sub.1 is --OH, --NH.sub.2, TABLE-US-00080 Gly-Z.sub.2, Gly Gly -Z.sub.2, Gly Gly Xaa.sub.31-Z.sub.2, Gly Gly Xaa.sub.31 Ser-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36 Xaa.sub.37-Z.sub.2 or Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36 Xaa.sub.37 Xaa.sub.38- Z.sub.2; wherein Xaa.sub.31, Xaa.sub.36, Xaa.sub.37 and Xaa.sub.38 are independently selected from the group consisting of Pro, homo- proline, thioproline and N-alkylglycine; and Z.sub.2 is --OH or --NH.sub.2; provided that no more than three of X.sub.aa3, X.sub.aa5, X.sub.aa6, X.sub.aa8, X.sub.aa10, X.sub.aa11, X.sub.aa12, X.sub.aa13, X.sub.aa14, X.sub.aa15, X.sub.aa16, X.sub.aa17, X.sub.aa19, X.sub.aa20, X.sub.aa21, X.sub.aa24, X.sub.aa25, X.sub.aa26, X.sub.aa27, and X.sub.aa28 are Ala; and a pharmaceutically acceptable salt thereof. 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 TABLE-US-00081 Xaa.sub.1 Xaa.sub.2 Xaa.sub.3 Gly Xaa.sub.5 Xaa.sub.6 Xaa.sub.7 Xaa.sub.8 Xaa.sub.9 Xaa.sub.10 Xaa.sub.11 Xaa.sub.12 Xaa.sub.13 Xaa.sub.14 Xaa.sub.15 Xaa.sub.16 Xaa.sub.17 Ala Xaa.sub.19 Xaa.sub.20 Xaa.sub.21 Xaa.sub.22 Xaa.sub.23 Xaa.sub.24 Xaa.sub.25 Xaa.sub.26 X.sub.1-Z.sub.1; Wherein Xaa.sub.1 is His, Arg, Tyr or 4-imidazopropionyl; Xaa.sub.2 is Ser, Gly, Ala or Thr; Xaa.sub.3 is Asp or Glu; Xaa.sub.5 is Ala or Thr; Xaa.sub.6 is Ala, Phe, Tyr or naphthylalanine; Xaa.sub.7 is Thr or Ser; Xaa.sub.8 is Ala, Ser or Thr; Xaa.sub.9 is Asp or Glu; Xaa.sub.10 is Ala, Leu, Ile, Val, pentylglycine or Met; Xaa.sub.11 is Ala or Ser; Xaa.sub.12 is Ala or Lys; Xaa.sub.13 is Ala or Gln; Xaa.sub.14 is Ala, Leu, Ile, pentylglycine, Val or Met; Xaa.sub.15 is Ala or Glu; Xaa.sub.16 is Ala or Glu; Xaa.sub.17 is Ala or Glu; Xaa.sub.19 is Ala or Val; Xaa.sub.20 is Ala or Arg; Xaa.sub.21 is Ala, Leu or Lys-NH.sup..epsilon.-R Asn, Asn Lys- NH.sup..epsilon.-R; Lys-NH.sup..epsilon.-R Ala; Ala Lys-NH.sup..epsilon.-R wherein R is Lys, Arg, C.sub.1-C.sub.10 straight chain or branched alkanoyl or cycloalkylalkanoyl; Xaa.sub.22 is Phe, Tyr or naphthylalanine; Xaa.sub.23 is Ile, Val, Leu, pentylglycine or tert- butyl glycine; Xaa.sub.24 is Ala, Glu or Asp; Xaa.sub.25 is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa.sub.26 is Ala or Leu; X.sub.1 is Lys Asn, Asn Lys, Lys-NH.sup..epsilon.-R Asn, Asn Lys- NH.sup..epsilon.-R, Lys-NH.sup..epsilon.-R Ala, Ala Lys-NH.sup..epsilon.-R wherein R is Lys, Arg, C.sub.1-C.sub.10 straight chain or branched alkanoyl or cycloalkylalkanoyl; and Z.sub.1 is --OH, --NH.sub.2, TABLE-US-00082 Gly-Z.sub.2, Gly Gly-Z.sub.2 Gly Gly Xaa.sub.31-Z.sub.2, Gly Gly Xaa.sub.31 Ser-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36-Z.sub.2, Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36 Xaa.sub.37-Z.sub.2 or Gly Gly Xaa.sub.31 Ser Ser Gly Ala Xaa.sub.36 Xaa.sub.37 Xaa.sub.38- Z.sub.2; wherein Xaa.sub.31, Xaa.sub.36, Xaa.sub.37 and Xaa.sub.38 are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine; and Z.sub.2 is --OH or --NH.sub.2; provided that no more than three of X.sub.aa3, X.sub.aa5, X.sub.aa6, X.sub.aa8, X.sub.aa10, X.sub.aa11, X.sub.aa12, X.sub.aa13, X.sub.aa14, X.sub.aa15, X.sub.aa16, X.sub.aa17, X.sub.aa19, X.sub.aa20, X.sub.aa21, X.sub.aa24, X.sub.aa25, X.sub.aa26, X.sub.aa27, and X.sub.aa28 are Ala; and a pharmaceutically acceptable salt thereof. 34. The compound according to claim 33 wherein X.sub.aa1 is His, Tyr, or 4-imidazopropionyl. 35. The compound according to claim 34 wherein X.sub.aa1 is His. 36. The compound according to claim 34 wherein X.sub.aa1 is 4-imidazopropionyl. 37. The compound according to claim 33 wherein X.sub.aa2 is Gly. 38. The compound according to claim 33 wherein X.sub.aa14 is Leu, pentylglycine, or Met. 39. The compound according to claim 33 wherein X.sub.aa25 is Trp or Phe. 40. The compound according to claim 33 wherein X.sub.aa6 is Phe or naphthylalanine; X.sub.aa22 is Phe or naphthylalanine; and X.sub.aa23 is Ile or Val. 41. The compound according to claim 33 wherein Z.sub.1 is --NH.sub.2. 42. The compound according to claim 33 wherein X.sub.aa31, X.sub.aa36, X.sub.aa37 and X.sub.aa38 are independently selected from the group consisting of Pro, homoproline, thioproline, and N-alkylalanine. 43. The compound according to claim 33 wherein Z.sub.2--NH.sub.2. 44. The A compound according to claim 33 wherein X.sub.1 is Lys Asn, Lys-NH.sup..epsilon.--R Asn, or Lys-NH.sup..epsilon.--R Ala wherein R is Lys, Arg, C.sub.1-C.sub.10 straight chain or branched alkanoyl. 45. The compound according to claim 33 wherein X.sub.aa21 is Lys-NH.sup..epsilon.--R where R is Lys, Arg, C.sub.1-C.sub.10 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.