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Claims for Patent: 5,686,411

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Claims for Patent: 5,686,411

Title: Amylin agonist peptides and uses therefor
Abstract:Agonist analogues of amylin and related pharmaceutical compositions, and methods of treatment of diabetes and other insulin-requiring states, as well as methods of treatment of hypoglycemia, are provided.
Inventor(s): Gaeta; Laura S. L. (Foster City, CA), Jones; Howard (Poway, CA), Albrecht; Elisabeth (San Diego, CA)
Assignee: Amylin Pharmaceuticals, Inc. (San Diego, CA)
Application Number:08/447,849
Patent Claims: 1. An agonist analogue of amylin having the amino acid sequence: ##STR1## wherein A.sub.1 is Lys, Ala, Ser or hydrogen;

B.sub.1 is Ala, Ser or Thr;

C.sub.1 is Val, Leu or Ile;

D.sub.1 is His or Arg;

E.sub.1 is Ser or Thr;

F.sub.1 is Ser, Thr, Gln or Asn;

G.sub.1 is Asn, Gln or His;

H.sub.1 is Phe, Leu or Tyr;

I.sub.1 is Ile, Val, Ala or Leu;

J.sub.1 is Ser, Pro or Thr;

K.sub.1 is Asn, Asp or Gln;

X and Y are independently selected amino acid residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage is a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val, J.sub.1 is Pro, and K.sub.1 is Asn; then one or more of A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

2. An agonist analogue of amylin according to claim 1 wherein X and Y are Cys residues linked by a disulfide bond.

3. An agonist analogue of amylin according to claim 2 wherein Z is amino.

4. An agonist analogue of amylin having the amino acid sequence: ##STR2## wherein A.sub.1 is Lys, Ala, Ser or hydrogen;

B.sub.1 is Ala, Ser or Thr;

C.sub.1 is Val, Leu or Ile;

D.sub.1 is His or Arg;

E.sub.1 is Ser or Thr;

F.sub.1 is Ser, Thr, Gln or Asn;

G.sub.1 is Asn, Gln or His;

H.sub.1 is Phe, Leu or Tyr;

I.sub.1 is Ile, Val, Ala or Leu;

J.sub.1 is Ser, Pro, Leu, Ile or Thr;

K.sub.1 is Asn, Asp or Gln;

X and Y are independently selected amino acid residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage is a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when

(a) A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val, J.sub.1 is Pro and K.sub.1 is Asn; or

(b) A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is His, E.sub.1 is Ser, F.sub.1 is Asn, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val, J.sub.1 is Ser and K.sub.1 is Asn;

then one or more of A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

5. An agonist analogue of amylin according to claim 4 wherein X and Y are Cys residues linked by a disulfide bond.

6. An agonist analogue of amylin according to claim 5 wherein Z is amino.

7. An agonist analogue of amylin having the amino acid sequence: ##STR3## wherein A.sub.1 is Lys, Ala, Ser or hydrogen;

B.sub.1 is Ala, Ser or Thr;

C.sub.1 is Val, Leu or Ile;

D.sub.1 is His or Arg;

E.sub.1 is Ser or Thr;

F.sub.1 is Ser, Thr, Gln or Asn;

G.sub.1 is Asn, Gln or His;

H.sub.1 is Phe, Leu or Tyr;

I.sub.1 is Ala or Pro;

J.sub.1 is Ile, Val, Ala or Leu;

K.sub.1 is Asn, Asp or Gln; X and Y are independently selected amino acid residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage is a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Pro, J.sub.1 is Val and K.sub.1 is Asn; then one or more of A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of aralkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

8. An agonist analogue of amylin according to claim 7 wherein X and Y are Cys residues linked by a disulfide bond.

9. An agonist analogue of amylin according to claim 8 wherein Z is amino.

10. An agonist analogue of amylin having the amino acid sequence: ##STR4## wherein A.sub.1 is Lys, Ala, Ser or hydrogen;

B.sub.1 is Ala, Ser or Thr;

C.sub.1 is Val, Leu or Ile;

D.sub.1 is His or Arg;

E.sub.1 is Ser or Thr;

F.sub.1 is Ser, Thr, Gln or Asn;

G.sub.1 is Asn, Gln or His;

H.sub.1 is Phe, Leu or Tyr;

I.sub.1 is Ile, Val, Ala or Leu;

J.sub.1 is Asn, Asp or Gln; X and Y are independently selected amino acid residues having side chains which are chemically bonded to each other to form an intramolecular linkage wherein said intramolecular linkage is a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A.sub.1 is Lys, B.sub.1 is Ala, C.sub.1 is Val, D.sub.1 is Arg, E.sub.1 is Ser, F.sub.1 is Ser, G.sub.1 is Asn, H.sub.1 is Leu, I.sub.1 is Val and J.sub.1 is Asn; then one or more of A.sub.1 to K.sub.1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

11. An agonist analogue of amylin according to claim 10 wherein X and Y are Cys residues linked by a disulfide bond.

12. An agonist analogue of amylin according to claim 11 wherein Z is amino.

13. An agonist analogue of amylin according to any of claims 1-12 wherein D.sub.1 is Arg.

14. An agonist analogue of amylin according to any of claims 1-6 or 10-12 wherein I.sub.1 is Val.

15. An agonist analogue of amylin according to any of claims 7-9 where J.sub.1 is Val.

16. An agonist analogue of amylin according to any of claims 1-12 wherein A.sub.1 is hydrogen.

17. .sup.18 Arg.sup.25,28 Pro-h-amylin.

18. des-.sup.1 Lys.sup.18 Arg.sup.25,28 Pro-h-amylin.

19. .sup.25,28,29 Pro-h-amylin.

20. des-.sup.1 Lys.sup.25,28,29 Pro-h-amylin.

21. .sup.18 Arg.sup.25,28,29 Pro-h-amylin.

22. des-.sup.1 Lys.sup.18 Arg.sup.25,28,29 Pro-h-amylin.

23. .sup.25 Pro.sup.26 Val.sup.28,29 Pro-h-amylin.

24. An agonist analogue of amylin according to any of claims 1-16 which is an acetate salt.

25. An agonist analogue of amylin according to any of claims 1-16 which is a trifluoroacetate salt.

26. An agonist analogue of amylin according to any of claims 1-16 which is a hydrochloride salt.

27. A compound according to any of claims 17-23 which is an acetate salt.

28. A compound according to any of claims 17-23 which is a trifluoroacetate salt.

29. A compound according to any of claims 17-23 which is a hydrochloride salt.

30. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of an agonist analogue of amylin according to claim 3.

31. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of an agonist analogue of amylin according to claim 6.

32. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of an agonist analogue of amylin according to claim 9.

33. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of an agonist analogue of amylin according to claim 12.

34. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of an agonist analogue of amylin according to any of claims 17-23.

35. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of .sup.25,28,29 Pro-h-amylin.

36. The method of any of claims 30-35 further comprising the administration to said mammal of a therapeutically effective amount of an insulin.

37. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of .sup.25,28,29 Pro-h-amylin and a therapeutically effective amount of an insulin.

38. A composition comprising a therapeutically effective amount of an agonist analogue of amylin according to claim 3 in a pharmaceutically acceptable carrier.

39. A composition comprising a therapeutically effective amount of an agonist analogue of amylin according to claim 6 in a pharmaceutically acceptable carrier.

40. A composition comprising a therapeutically effective amount of an agonist analogue of amylin according to claim 9 in a pharmaceutically acceptable carrier.

41. A composition comprising a therapeutically effective amount of an agonist analogue of amylin according to claim 12 in a pharmaceutically acceptable carrier.

42. A composition comprising a therapeutically effective amount of an agonist analogue of amylin according to any of claims 17-23 in a pharmaceutically acceptable carrier.

43. A composition comprising a therapeutically effective amount of .sup.25,28,29 Pro-h-amylin in a pharmaceutically acceptable carrier.

44. A composition comprising a therapeutically effective amount of an agonist analogue of amylin according to any of claims 3, 6, 9, 11 and 17-23 and an insulin admixed in a pharmaceutically acceptable carrier.

45. A composition comprising a therapeutically effective amount of .sup.25,28,29 Pro-h-amylin and an insulin admixed in a pharmaceutically acceptable carrier.
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