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Claims for Patent: 6,114,304

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Claims for Patent: 6,114,304

Title: Methods for regulating gastrointestinal motility
Abstract:Methods for treating conditions associated with elevated, inappropriate or undesired post-prandial blood glucose levels are disclosed which comprise administration of an effective amount of an amylin agonist alone or in conjunction with other anti-gastric emptying agents. Methods for reducing gastric motility and delaying gastric emptying for therapeutic and diagnostic purposes are also described.
Inventor(s): Kolterman; Orville G. (Poway, CA), Young; Andrew A. (Alpine, CA), Rink; Timothy J. (La Jolla, CA), Brown; Kathleen Ann Keiting (Wake Forest, NC)
Assignee: Amylin Pharmaceuticals, Inc. (San Diego, CA)
Application Number:08/302,069
Patent Claims: 1. A method of reducing gastric motility or delaying gastric emptying in a mammal comprising administering to said mammal a therapeutically effective amount of an amylin or an amylin agonist, wherein said amylin agonist is an amylin agonist analogue having the following amino acid sequence:

.sup.1 A.sub.1 -X-Asn-Thr-.sup.5 Ala-Thr-Y-Ala-Thr-.sup.10 Gln-Arg-Leu-B.sub.1 -Asn-.sup.15 Phe-Leu-C.sub.1 -D.sub.1 -E.sub.1 -.sup.20 F.sub.1 -G.sub.1 -Asn-H.sub.1 -Gly-.sup.25 Pro-I.sub.1 -Leu-Pro-J.sub.1 -.sup.30 Thr-K.sub.1 -Val-Gly-Ser-.sup.35 Asn-Thr-Tyr-Z

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 residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises 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, 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. A method according to claim 1 wherein X and Y comprise Cys residues linked by a disulfide bond.

3. A method according to claim 2 wherein Z is amino.

4. A method of reducing gastric motility or delaying gastric emptying in a mammal comprising administering to said mammal a therapeutically effective amount of an amylin or an amylin agonist, wherein said amylin agonist is an amylin agonist analogue having the following amino acid sequence:

.sup.1 A.sub.1 -X-Asn-Thr-.sup.5 Ala-Thr-Y-Ala-Thr-.sup.10 Gln-Arg-Leu-B.sub.1 -Asn-.sup.15 Phe-Leu-C.sub.1 -D.sub.1 -E.sub.1 -.sup.20 F.sub.1 -G.sub.1 -Asn-H.sub.1 -Gly-25Pro-I.sub.1 -Leu-J.sub.1 -Pro-30Thr-K.sub.1 -Val-Gly-Ser-.sup.35 Asn-Thr-Tyr-Z

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 residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided than 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. A method according to claim 4 wherein X and Y comprise Cys residues linked by a disulfide bond.

6. A method according to claim 5 wherein Z is amino.

7. A method of reducing gastric motility or delaying gastric emptying in a mammal comprising administering to said mammal a therapeutically effective amount of an amylin or an amylin agonist, wherein said amylin agonist is an amylin agonist analogue having the following amino acid sequence:

.sup.1 A.sub.1 -X-Asn-Thr-.sup.5 Ala-Thr-Y-Ala-Thr-.sup.10 Gln-Arg-Leu-B.sub.1 -Asn-.sup.15 Phe-Leu-C.sub.1 -D.sub.1 -E.sub.1 -.sup.20 F.sub.1 -G.sub.1 -Asn-H.sub.1 -Gly-.sup.25 I.sub.1 -J.sub.1 -Leu-Pro-Pro-.sup.30 Thr-K.sub.1 -Val-Gly-Ser-.sup.35 Asn-Thr-Tyr-Z

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 residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises 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 alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

8. A method according to claim 7 wherein X and Y comprise Cys residues linked by a disulfide bond.

9. A method according to claim 8 wherein Z is amino.

10. A method of reducing gastric motility or delaying gastric emptying in a mammal comprising administering to said mammal a therapeutically effective amount of an amylin or an amylin agonist, wherein said amylin agonist is an amylin agonist analogue having the following amino acid sequence:

.sup.1 A.sub.1 -X-Asn-Thr-.sup.5 Ala -Thr-Y-Ala-Thr-.sup.10 Gln-Arg-Leu-B.sub.1 -Asn-.sup.15 Phe-Leu-C.sub.1 -D.sub.1 -E.sub.1 -.sup.20 F.sub.1 -G.sub.1 -Asn-H.sub.1 -Gly-.sup.25 Pro-I.sub.1 -Leu-Pro-Pro-.sup.30 Thr-J.sub.1 -Val-Gly-Ser-.sup.35 Asn-Thr-Tyr-Z

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 residues having side chains which are chemically bonded to each other to form an intramolecular linkage wherein said intramolecular linkage comprises 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. A method according to claim 10 wherein X and Y comprise Cys residues linked by a disulfide bond.

12. A method according to claim 11 wherein Z is amino.

13. A method according to any of claims 1-12 wherein D.sub.1 is Arg.

14. An method according to any of claims 7-9 wherein J.sub.1 is Val.

15. A method according to any of claims 1-6 or 10-12 wherein I.sub.1 is Val.

16. A method according to any of claims 1-12 wherein A.sub.1 is hydrogen.

17. A method according to any of claims 1-12 wherein said amylin agonist is .sup.18 Arg.sup.25,28 Pro-h-amylin.

18. A method according to any of claims 1-12 wherein said amylin agonist is des-.sup.1 Lys.sup.18 Arg.sup.25,28 Pro-h-amylin.

19. A method according to any of claims 1-12 wherein said amylin agonist is .sup.25,28,29 Pro-h-amylin.

20. A method according to any of claims 1-12 wherein said amylin agonist is des-.sup.1 Lys.sup.25,28,29 Pro-h-amylin.

21. A method according to any of claims 1-12 wherein said amylin agonist is .sup.18 Arg.sup.25,28,29 Pro-h-amylin.

22. A method according to any of claims 1-12 wherein said amylin agonist is des-.sup.1 Lys.sup.18 Arg.sup.25,28,29 Pro-h-amylin.

23. A method according to any of claims 1-12 wherein said amylin agonist is .sup.25 Pro.sup.26 Val.sup.28,29 Pro-h-amylin.

24. A method according to any of claims 1-12 wherein said amylin agonist is an acetate salt.

25. A method according to any of claims 1-12 wherein said amylin agonist is a hydrochloride salt.

26. A method according to any of claims 1, 4, 7 or 10 wherein said mammal is undergoing a gastrointestinal diagnostic procedure.

27. A method according to claim 26 wherein said gastrointestinal diagnostic procedure is a radiological examination.

28. A method according to claim 27 wherein said gastrointestinal diagnostic procedure is magnetic resonance imaging.

29. A method according to any of claims 1, 4, 7 or 10 wherein said gastric motility is associated with gastrointestinal disorder.

30. A method according to claim 29 wherein said gastrointestinal disorder is spasm.

31. A method according to claim 30 wherein said spasm is associated with a disorder selected from the group consisting of acute diverticulitis or a disorder of the biliary tract or a disorder of the Sphincter of Oddi.

32. A method of treating postprandial dumping syndrome in a subject comprising administering to said subject an amount of an amylin agonist effective to induce amylin activity in said mammal, wherein said amylin agonist is an amylin analog according to any of claims 1-12.

33. A method according to claim 32 wherein said amylin agonist is .sup.25,28,29 Pro-h-amylin.

34. A method of treating postprandial hyperglycemia in a subject comprising administering to said subject an amount of an amylin agonist effective to induce amylin activity in said mammal, wherein said amylin agonist is an amylin analog according to any of claims 1-12.

35. A method according to claim 34 wherein said amylin agonist is .sup.25,28,29 Pro-h-amylin.
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