Methods for regulating gastrointestinal motility

• US 6,114,304 A
• Filed: 09/07/1994
• Issued: 09/05/2000
• Est. Priority Date: 09/07/1993
• Status: Expired due to Term

• Current Assignee: Astrazeneca Pharmaceuticals LP (Astrazeneca PLC)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Brown, Kathleen Ann Keiting, Young, Andrew A., Kolterman, Orville G., Rink, Timothy J.
• Primary Examiner(s): CELSA, BENNETT M
• Application Number:
  US08/302,069
• Time in Patent Office: 2,190 Days
• Field of Search: 514/12, 514/3
• US Class Current: 424/9.3
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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.

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:

¹ A₁ -X-Asn-Thr-⁵ Ala-Thr-Y-Ala-Thr-¹⁰ Gln-Arg-Leu-B₁ -Asn-¹⁵ Phe-Leu-C₁ -D₁ -E₁ -²⁰ F₁ -G₁ -Asn-H₁ -Gly-²⁵ Pro-I₁ -Leu-Pro-J₁ -³⁰ Thr-K₁ -Val-Gly-Ser-³⁵ Asn-Thr-Tyr-Z

wherein

A₁ is Lys, Ala, Ser or hydrogen;

B₁ is Ala, Ser or Thr;

C₁ is Val, Leu or Ile;

D₁ is His or Arg;

E₁ is Ser or Thr;

F₁ is Ser, Thr, Gln or Asn;

G₁ is Asn, Gln or His;

H₁ is Phe, Leu or Tyr;

I₁ is Ile, Val, Ala or Leu;

J₁ is Ser, Pro or Thr;

K₁ 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 A₁ is Lys, B₁ is Ala, C₁ is Val, D₁ is Arg, E₁ is Ser, F₁ is Ser, G₁ is Asn, H, is Leu, I₁ is Val, J₁ is Pro, and K₁ is Asn;

then one or more of A₁ to K₁ 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.

13. A method according to any of claims 1-12 wherein D₁ is Arg.

15. A method according to any of claims 1-6 or 10-12 wherein I₁ is Val.

16. A method according to any of claims 1-12 wherein A₁ is hydrogen.

17. A method according to any of claims 1-12 wherein said amylin agonist is ¹⁸ Arg²⁵,28 Pro-h-amylin.

18. A method according to any of claims 1-12 wherein said amylin agonist is des-¹ Lys¹⁸ Arg²⁵,28 Pro-h-amylin.

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

20. A method according to any of claims 1-12 wherein said amylin agonist is des-¹ Lys²⁵,28,29 Pro-h-amylin.

21. A method according to any of claims 1-12 wherein said amylin agonist is ¹⁸ Arg²⁵,28,29 Pro-h-amylin.

22. A method according to any of claims 1-12 wherein said amylin agonist is des-¹ Lys¹⁸ Arg²⁵,28,29 Pro-h-amylin.

23. A method according to any of claims 1-12 wherein said amylin agonist is ²⁵ Pro²⁶ Val²⁸,29 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 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 ²⁵,28,29 Pro-h-amylin.

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:

¹ A₁ -X-Asn-Thr-⁵ Ala-Thr-Y-Ala-Thr-¹⁰ Gln-Arg-Leu-B₁ -Asn-¹⁵ Phe-Leu-C₁ -D₁ -E₁ -²⁰ F₁ -G₁ -Asn-H₁ -Gly-25Pro-I₁ -Leu-J₁ -Pro-30Thr-K₁ -Val-Gly-Ser-³⁵ Asn-Thr-Tyr-Z

wherein

A₁ is Lys, Ala, Ser or hydrogen;

B₁ is Ala, Ser or Thr;

C₁ is Val, Leu or Ile;

D₁ is His or Arg;

E₁ is Ser or Thr;

F₁ is Ser, Thr, Gln or Asn;

G₁ is Asn, Gln or His;

H₁ is Phe, Leu or Tyr;

I₁ is Ile, Val, Ala or Leu;

J₁ is Ser, Pro, Leu, Ile or Thr;

K₁ 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) A₁ is Lys, B₁ is Ala, C₁ is Val, D₁ is Arg, E₁ is Ser, F₁ is Ser, G₁ is Asn, H₁ is Leu, I₁ is Val, J₁ is Pro and K₁ is Asn;

or

(b) A₁ is Lys, B₁ is Ala, C₁ is Val, D₁ is His, E₁ is Ser, F₁ is Asn, G₁ is Asn, H₁ is Leu, I₁ is Val, J₁ is Ser and K₁ is Asn;

then one or more of A₁ to K₁ 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:

¹ A₁ -X-Asn-Thr-⁵ Ala-Thr-Y-Ala-Thr-¹⁰ Gln-Arg-Leu-B₁ -Asn-¹⁵ Phe-Leu-C₁ -D₁ -E₁ -²⁰ F₁ -G₁ -Asn-H₁ -Gly-²⁵ I₁ -J₁ -Leu-Pro-Pro-³⁰ Thr-K₁ -Val-Gly-Ser-³⁵ Asn-Thr-Tyr-Z

wherein

A₁ is Lys, Ala, Ser or hydrogen;

B₁ is Ala, Ser or Thr;

C₁ is Val, Leu or Ile;

D₁ is His or Arg;

E₁ is Ser or Thr;

F₁ is Ser, Thr, Gln or Asn;

G₁ is Asn, Gln or His;

H₁ is Phe, Leu or Tyr;

I₁ is Ala or Pro;

J₁ is Ile, Val, Ala or Leu;

K₁ 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 A₁ is Lys, B₁ is Ala, C₁ is Val, D₁ is Arg, E₁ is Ser, F₁ is Ser, G₁ is Asn, H₁ is Leu, I₁ is Pro, J₁ is Val and K₁ is Asn;

then one or more of A₁ to K₁ 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.

14. An method according to any of claims 7-9 wherein J₁ is Val.

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:

¹ A₁ -X-Asn-Thr-⁵ Ala -Thr-Y-Ala-Thr-¹⁰ Gln-Arg-Leu-B₁ -Asn-¹⁵ Phe-Leu-C₁ -D₁ -E₁ -²⁰ F₁ -G₁ -Asn-H₁ -Gly-²⁵ Pro-I₁ -Leu-Pro-Pro-³⁰ Thr-J₁ -Val-Gly-Ser-³⁵ Asn-Thr-Tyr-Z

wherein

A₁ is Lys, Ala, Ser or hydrogen;

B₁ is Ala, Ser or Thr;

C₁ is Val, Leu or Ile;

D₁ is His or Arg;

E₁ is Ser or Thr;

F₁ is Ser, Thr, Gln or Asn;

G₁ is Asn, Gln or His;

H₁ is Phe, Leu or Tyr;

I₁ is Ile, Val, Ala or Leu;

J₁ 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 A₁ is Lys, B₁ is Ala, C₁ is Val, D₁ is Arg, E₁ is Ser, F₁ is Ser, G₁ is Asn, H₁ is Leu, I₁ is Val and J₁ is Asn;

then one or more of A₁ to K₁ 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.