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Details for Patent: 7,220,721

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Details for Patent: 7,220,721

Title:Exendin agonist 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.
Inventor(s): Beeley; Nigel R. (Solana Beach, CA), Prickett; Kathryn S. (San Diego, CA)
Assignee: Amylin Pharmaceuticals, Inc. (San Diego, CA)
Filing Date:Nov 13, 1998
Application Number:09/554,531
Claims:1. A peptide compound or pharmaceutically acceptable salt, thereof, selected from: Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Xaa.sub.37-Xaa.sub.38-Xaa.sub.3- 9-Z.sub.2, (SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Xaa.sub.37-Xaa.sub.38-Z.sub.2, (residues 1 38 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Xaa.sub.37-Z.sub.2, (residues 1 37 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Z.sub.2, (residues 1 36 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Z.sub.2, (residues 1 35 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Z.sub.2, (residues 1 34 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Z.sub.2, (residues 1 33 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Z.sub.2, (residues 1 32 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Z.sub.2, (residues 1 31 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Z.sub.2, (residues 1 30 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Z.sub.2, (residues 1 29 of SEQ ID NO:4)-Z.sub.2; and Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Z.s- ub.2, (residues 1 28 of SEQ ID NO:4)-Z.sub.2; wherein: Xaa.sub.1 is His, Arg, Tyr, Ala, Norval, Val or Norleu; Xaa.sub.2 is Ser, Gly, Ala or Thr; Xaa.sub.3 and Xaa.sub.24 are each independently Ala, Asp or Glu; Xaa.sub.4 is Ala, Norval, Val, Norleu or Gly; 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 Ala, Norval, Val, Norleu, Asp or Glu; Xaa.sub.10 and Xaa.sub.14 are each independently Ala, Leu, Ile, Val, pentylglycine or Met; Xaa.sub.11 is Ala or Ser; Xaa.sub.12 and Xaa.sub.27 are each independently Ala or Lys; Xaa.sub.13 is Ala or Gln; Xaa.sub.15, Xaa.sub.16 and Xaa.sub.17 are each independently Ala or Glu; Xaa.sub.19 is Ala or Val; Xaa.sub.20 is Ala or Arg; Xaa.sub.21 and Xaa.sub.26 are each independently 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.25 is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa.sub.28 is Ala or Asn; Xaa.sub.31, Xaa.sub.36, Xaa.sub.37, and Xaa.sub.38 are each independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglcine or N-alkylalanine; X.sub.39 is Ser or Tyr; Z.sub.2 is --OH or --NH.sub.2; and provided that no more than three of Xaa.sub.3, Xaa.sub.4, Xaa.sub.5, Xaa.sub.6, 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, Xaa.sub.19, Xaa.sub.20, Xaa.sub.21, Xaa.sub.24, Xaa.sub.25, Xaa.sub.26, Xaa.sub.27 and Xaa.sub.28 are Ala; and provided also that if Xaa.sub.1 is His, Arg or Tyr, then at least one of Xaa.sub.3, Xaa.sub.4 and Xaa.sub.9 is Ala.

2. The compound according to claim 1 wherein Xaa.sub.1 is His, Ala or Norval.

3. The compound according to claim 1 wherein Xaa.sub.1 is Ala.

4. The compound according to claim 2 wherein Xaa.sub.1 is Ala.

5. The compound according to claim 1 wherein Xaa.sub.1 is His.

6. The compound according to claim 2 wherein Xaa.sub.1 is His.

7. The compound according to claim 1 wherein Xaa.sub.2 is Gly.

8. The compound according to claim 2 wherein Xaa.sub.2 is Gly.

9. The compound according to claim 1 wherein Xaa.sub.3 is Ala.

10. The compound according to claim 2 where Xaa.sub.3 is Ala.

11. The compound according to claim 1 wherein Xaa.sub.4 is Ala.

12. The compound according to claim 2 where Xaa.sub.4 is Ala.

13. The compound according to claim 1 wherein Xaa.sub.9 is Ala.

14. The compound according to claim 2 where Xaa.sub.9 is Ala.

15. The compound according to any of claims 8 14 wherein Xaa.sub.14 is Leu, pentylglycine or Met.

16. The compound according to claim 15 wherein Xaa.sub.25 is Trp or Phe.

17. The compound according to claim 16 wherein Xaa.sub.6 is Ala, Phe or naphthylalanine; Xaa.sub.22 is Phe or naphthylalanine; and Xaa.sub.23 is Ile or Val.

18. The compound according to claim 17 wherein the peptide is Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-NH.- sub.2, (residues 1 28 of SEQ ID NO:4)-NH.sub.2.

19. The compound according to claim 17 wherein Xaa.sub.31, Xaa.sub.36, Xaa.sub.37 and Xaa.sub.38a are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine.

20. The compound according to claim 1 wherein Xaa.sub.39 is Ser or Tyr.

21. The compound according to claim 17 wherein Xaa.sub.39 is Ser or Tyr.

22. The compound according to claim 1 wherein Xaa.sub.39 is Ser.

23. The compound according to claim 17 wherein Xaa.sub.39 is Ser.

24. The compound according to claim 1 wherein Z.sub.2 is --NH.sub.2.

25. The compound according to claim 19, where Z.sub.2 is --NH.sub.2.

26. The compound according to claim 21, where Z.sub.2 is --NH.sub.2.

27. The compound according to claim 23, where Z.sub.2 is --NH.sub.2.

28. The compound according to claim 1 wherein the peptide is Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-NH.- sub.2, (residues 1 28 of SEQ ID NO:4)-NH.sub.2.

29. The compound according to claim 1 wherein Xaa.sub.31, Xaa.sub.36, Xaa.sub.37 and Xaa.sub.38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine.

30. The compound according to claim 1 which has an amino acid sequence selected from SEQ. ID. NOS. 5 to 93.

31. A peptide compound or pharmaceutically acceptable salt, thereof, selected from: Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Xaa.sub.37-Xaa.sub.38-Z.sub.2, (residues 1 38 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Xaa.sub.37-Z.sub.2, (residues 1 37 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Z.sub.2, (residues 1 36 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Z.sub.2, (residues 1 35 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Gly-Z.sub.2, (residues 1 34 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Ser-Z.sub.2, (residues 1 33 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Ser-Z.sub.2, (residues 1 32 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Xaa.sub.31-Z.sub.2, (residues 1 31 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Gly-Z.sub.2, (residues 1 30 of SEQ ID NO:4)-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Gly- -Z.sub.2, (residues 1 29 of SEQ ID NO:4)-Z.sub.2; and Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-Xaa.sub.27-Xaa.sub.28-Z.s- ub.2, (residues 1 28 of SEQ ID NO:4)-Z.sub.2; wherein: Xaa.sub.1 is His or Ala; Xaa.sub.2 is Gly or Ala; Xaa.sub.3 and Xaa.sub.24 are each independently Ala, Asp or Glu; Xaa.sub.4 is Ala or Gly; Xaa.sub.5 is Ala or Thr; Xaa.sub.6 is Ala, Phe or naphthylalanine; Xaa.sub.7 is Thr or Ser; Xaa.sub.8 is Ala, Ser or Thr; Xaa.sub.9 is Ala, Asp or Glu; Xaa.sub.10 is Ala, Leu or pentylglycine; Xaa.sub.11 is Ala or Ser; Xaa.sub.12 and Xaa.sub.27 are each independently Ala or Lys; Xaa.sub.13 is Ala or Gln; Xaa.sub.14 is Ala, Leu, Met or pentylglycine; Xaa.sub.15, Xaa.sub.16 and Xaa.sub.17 are each independently Ala or Glu; Xaa.sub.19 is Ala or Val; Xaa.sub.20 is Ala or Arg; Xaa.sub.21 and Xaa.sub.26 are each independently Ala or Leu; Xaa.sub.22 is Phe or naphthylalanine; Xaa.sub.23 is Ile, Val or tert-butylglycine; Xaa.sub.25 is Ala, Trp or Phe; Xaa.sub.28 is Ala or Asn; Xaa.sub.31, Xaa.sub.36, Xaa.sub.37, and Xaa.sub.38 are each independently Pro, homoproline, thioproline, N-methylalanine; Z.sub.2 is --OH or --NH.sub.2; and provided that no more than three of Xaa.sub.3, Xaa.sub.4, Xaa.sub.5, Xaa.sub.6 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, Xaa.sub.19, Xaa.sub.20, Xaa.sub.21, Xaa.sub.24, Xaa.sub.25, Xaa.sub.26, Xaa.sub.27 and Xaa.sub.28 are Ala; and provided also that if Xaa.sub.1 is His then at least one of Xaa.sub.3, Xaa.sub.4 and Xaa.sub.9 is Ala.

32. The compound according to claim 31 which has an amino acid sequence selected from SEQ. ID. NOS. 5 9.

33. A composition comprising a compound of any one of claims 1 to 14, 20, 22, 24 and 28 to 31 in a pharmaceutically acceptable carrier.

34. A composition comprising a compound of claim 32 in a pharmaceutically acceptable carrier.

35. A method for the treatment of diabetes mellitus comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1.

36. A method for the treatment of diabetes mellitus comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 30.

37. A method for the treatment of diabetes mellitus comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 31.

38. The method of claim 35 further comprising administering a therapeutically effective amount of an insulin.

39. The method of claim 36 further comprising administering a therapeutically effective amount of an insulin.

40. The method of claim 37 further comprising administering a therapeutically effective amount of an insulin.

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

42. A method for the treatment of a hyperglycemic condition in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a compound according to claim 30.

43. A method for the treatment of a hyperglycemic condition in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a compound according to claim 31.

44. A compound or pharmaceutically acceptable salt, thereof, selected from: Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Gly-Gly-Xaa- .sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Xaa.sub.37-Xaa.sub.38-Xaa.sub.39-Z.sub.- 2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-Xaa.sub.5-Xaa.sub.6-Xaa.sub.7-X- aa.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-G- ly-Gly-Xaa.sub.31-Ser-Ser-Gly-Ala-Xaa.sub.36-Xaa.sub.37-Xaa.sub.38-Z.sub.2- ; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-Xaa.sub.5-Xaa.sub.6-Xaa.sub.7-Xa- a.sub.8-Xaa.sub.9-Xaa.sub.10-Xaa.sub.11-Xaa.sub.12-Xaa.sub.13-Xaa.sub.14-X- aa.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.s- ub.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-Gly-Gly-Xaa.sub.- 31-Ser-Ser-Gly-Ala-Xaa.sub.36-Xaa.sub.37-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-Gly-Gly-Xaa.sub.3- 1-Ser-Ser-Gly-Ala-Xaa.sub.36-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-Gly-Gly-Xaa.sub.3- 1-Ser-Ser-Gly-Ala-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-Gly-Gly-Xaa.sub.3- 1-Ser-Ser-Gly-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-Gly-Gly-Xaa.sub.3- 1-Ser-Ser-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-Gly-Gly-Xaa.sub.3- 1-Ser-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-Gly-Gly-Xaa.sub.3- 1-Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Gly-Gly- -Z.sub.2; Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Gly-Z.su- b.2; and Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-Xaa.sub.5-Xaa.sub.6-Xaa.s- ub.7-Xaa.sub.8-Xaa.sub.9-Xaa.sub.10-Xaa.sub.11-Xaa.sub.12-Xaa.sub.13-Xaa.s- ub.14-Xaa.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.2- 1-Xaa.sub.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-Z.sub.2; wherein: Xaa.sub.1 is His, Arg, Tyr, Ala, Norval, Val, Norleu or 4-imidazolepropionyl; Xaa.sub.2 is Ser, Gly, Ala or Thr; Xaa.sub.3 and Xaa.sub.24 are each independently Ala, Asp or Glu; Xaa.sub.4 is Ala, Norval, Val, Norleu or Gly; 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 Ala, Norval, Val, Norleu, Asp or Glu; Xaa.sub.10 and Xaa.sub.14 are each independently 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.15, Xaa.sub.16 and Xaa.sub.17 are each independently 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(R), where R is attached to the .epsilon.-amine of lysine and is selected from the group consisting of 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, tert-butylglycine or Met; 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(R)-Asn, Lys(R)-Ala, Asn-Lys(R) and Ala-Lys(R), where R is attached to the .epsilon.-amine of lysine and is selected from the group consisting of Lys, Arg, C.sub.1 C.sub.10 straight chain or branched alkanoyl or cycloalkylalkanoyl; Xaa.sub.31, Xaa.sub.36, Xaa.sub.37, and Xaa.sub.38 are each independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglcine or N-alkylalanine; X.sub.39 is Ser or Tyr; Z.sub.2 is --OH or --NH.sub.2; and provided that no more than three of Xaa.sub.3, Xaa.sub.4, Xaa.sub.5, Xaa.sub.6, 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, Xaa.sub.19, Xaa.sub.20, Xaa.sub.21, Xaa.sub.24, Xaa.sub.25, Xaa.sub.26, Xaa.sub.27 and Xaa.sub.28 are Ala; and provided also that if Xaa.sub.1 is His, Arg, Tyr or 4-imidazolepropionyl, then at least one of Xaa.sub.3, Xaa.sub.4 and Xaa.sub.9 is Ala.

45. The compound according to claim 44 wherein Xaa.sub.1 is His, Ala, Norval or 4-imidazopropionyl.

46. The compound according to claim 45 wherein Xaa.sub.1 is His or 4-imidazopropionyl.

47. The compound according to claim 45 wherein Xaa.sub.1 is Ala.

48. The compound according to claim 45 wherein Xaa.sub.1 is His.

49. The compound according to claim 45 wherein Xaa.sub.1 is 4-imidazopropionyl.

50. The compound according to claim 44 wherein Xaa.sub.2 is Gly.

51. The compound according to any of claims 45 49 wherein Xaa.sub.2 is Gly.

52. The compound according to claim 44 wherein Xaa.sub.3 is Ala.

53. The compound according to any of claims 45 49 where Xaa.sub.3 is Ala.

54. The compound according to claim 44 wherein Xaa.sub.4 is Ala.

55. The compound according to any of claims 45 49 where Xaa.sub.4 is Ala.

56. The compound according to claim 44 wherein Xaa.sub.9 is Ala.

57. The compound according to any of claim 45 49 where Xaa.sub.9 is Ala.

58. The compound according to claim 44 wherein Xaa.sub.14 is Leu, pentylglycine or Met.

59. The compound according to claim 44 wherein Xaa.sub.25 is Trp or Phe.

60. The compound according to claim 44 wherein Xaa.sub.6 is Ala, Phe or naphthylalanine; Xaa.sub.22 is Phe or naphthylalanine; and Xaa.sub.23 is Ile or Val.

61. The compound according to claim 44 wherein the compound is Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-NH.sub.2.

62. The compound according to claim 44 wherein Xaa.sub.31, Xaa.sub.36, Xaa.sub.37 and Xaa.sub.38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine.

63. The compound according to claim 44 wherein Xaa.sub.39 is Ser or Tyr.

64. The compound according to claim 60 wherein Xaa.sub.39 is Ser or Tyr.

65. The compound according to claim 44 wherein Xaa.sub.39 is Ser.

66. The compound according to claim 60 wherein Xaa.sub.39 is Ser.

67. The compound according to claim 44 wherein Z.sub.2 is --NH.sub.2.

68. The compound according to any of claims 52, 54 or 56 wherein Z.sub.2 is --NH.sub.2.

69. The compound according to claim 44 wherein the compound is Xaa.sub.1-Xaa.sub.2-Xaa.sub.3-Xaa.sub.4-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-Xa- a.sub.15-Xaa.sub.16-Xaa.sub.17-Ala-Xaa.sub.19-Xaa.sub.20-Xaa.sub.21-Xaa.su- b.22-Xaa.sub.23-Xaa.sub.24-Xaa.sub.25-Xaa.sub.26-X.sub.1-OH.

70. The compound according to claim 44 wherein Xaa.sub.31, Xaa.sub.36, Xaa.sub.37 and Xaa.sub.38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine.

71. The compound according to claim 44 wherein X.sub.1 is Lys Asn, Lys-NH.sup..epsilon.-R Asn, or Lys-NH.sup..epsilon.-R Ala where R is Lys, Arg, C.sub.1 C.sub.10 straight chain or branched alkanoyl.

72. The compound according to claim 44 wherein Xaa.sub.21 is Lys-NH.sup..epsilon.-R where R is Lys, Arg, C.sub.1 C.sub.10 straight chain or branched alkanoyl or cycloalkyl-alkanoyl.

73. The compound according to claim 44 which has an amino acid sequence selected from SEQ. ID. NOS. 95 110.

74. A composition comprising a compound of claim 44 in a pharmaceutically acceptable carrier.

75. A composition comprising a compound of claim 73 in a pharmaceutically acceptable carrier.
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