Claims for Patent: 6,608,029

Summary for Patent: 6,608,029

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), Keating Brown; Kathleen Ann (Wake Forest, NC)
Assignee:	Amylin Pharmaceuticals, Inc. (San Diego, CA)
Application Number:	09/576,062
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.sup.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.sup.1 is His or Arg; E.sub.1 is Ser or Thr; F.sub.1 is Ser, Thr, Gln or Asn; G.sup.1 is Asn, Gln or His; H.sup.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) 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, H1 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; and wherein said agonist exhibits a nucleus accumbens receptor binding activity of 5 nM or less. 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. The method of claim 1 wherein said amylin agonist is administered parenterally. 5. The method of claim 1 wherein said agonist exhibits a nucleus accumbens receptor binding activity of 1 nM or less. 6. The method of claim 1 wherein said agonist exhibits a nucleus accumbens receptor binding activity of 50 pM or less. 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 Pro-I.sub.1 -Leu-J.sub.1 -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 Ile, Val, Ala or Leu; J.sub.1 is Ser, Pro, Leu, Ile or Thr; K.sub.1 K 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) 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; and wherein said agonist exhibits a nucleus accumbens receptor binding activity of 5 nM or less. 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. The method of claim 7 wherein said amylin agonist is administered parenterally. 11. The method of claim 7 wherein said agonist exhibits a nucleus accumbens receptor binding activity of 1 nM or less. 12. The method of claim 7 wherein said agonist exhibits a nucleus accumbens receptor binding activity of 50 pM or less. 13. 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; and wherein said agonist exhibits a nucleus accumbens receptor binding activity of 5 nM or less. 14. A method according to claim 13 wherein X and Y comprise Cys residues linked by a disulfide bond. 15. A method according to claim 14 wherein Z is amino. 16. The method of claim 13 wherein said amylin agonist is administered parenterally. 17. The method of claim 13 wherein said agonist exhibits a nucleus accumbens receptor binding activity of 1 nM or less. 18. The method of claim 13 wherein said agonist exhibits a nucleus accumbens receptor binding activity of 50 pM or less. 19. 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 lie, 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; and wherein said agonist exhibits a nucleus accumbens receptor binding activity of 5 nM or less. 20. The method of claim 19 wherein said amylin agonist is administered parenterally. 21. The method of claim 19 wherein said agonist exhibits a nucleus accumbens receptor binding activity of 1 nM or less. 22. The method of claim 19 wherein said agonist exhibits a nucleus accumbens receptor binding activity of 50 pM or less.