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):	Orville G. Kolterman, Andrew A. Young, Timothy J. Rink, Kathleen Ann Keating Brown
Assignee:	Amylin Pharmaceuticals LLC
Application Number:	US09/576,062
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: 1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1-20F1-G1-Asn-H1-Gly-25Pro-I1-Leu-Pro-J1-30Thr-K1-Val-Gly-Ser-35Asn-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; I1is 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 (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; 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: 1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1-20F1-G1-Asn-H1-Gly-25Pro-I1-Leu-J1-Pro-30Thr-K1-Val-Gly-Ser-35Asn-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 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) 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; 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: 1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1-20F1-G1-Asn-H1-Gly-25I1-J1-Leu-Pro-Pro-30Thr-K1-Val-Gly-Ser-35Asn-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; 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: 1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1-20F1-G1-Asn-H1-Gly-25Pro-I1-Leu-Pro-Pro-30Thr-J1-Val-Gly-Ser-35Asn-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 lie, 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; 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.