Claims for Patent: 7,407,934

Summary for Patent: 7,407,934

Title:	Methods for regulating postprandial blood glucose
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:	US10/643,681
Patent Claims:	1. A method of reducing or moderating a postprandial rise in plasma glucose in a mammal comprising administering to said mammal in need of reducing or moderating a postprandial rise in plasma glucose an amylin agonist analogue in an amount effective to reduce or moderate a postprandial rise in plasma glucose, wherein the amylin agonist analogue is a peptide having the amino acid sequence selected from the group consisting of a) 1A1-X-Asn-Thr-5-Ala-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 (SEQ ID NO:42) 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 that when (i) 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 (ii) 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, cycloaklyamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; b) 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 (SEQ ID NO:44) 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 (SEQ ID NO:41), 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; c) 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 (SEQ ID NO:45) 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; and 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; 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 (SEQ ID NO:41), then one or more of A1 to J1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and d) 1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1- D1-E1-20F1-G1Asn-H1-Gly-25I1-J1-Leu-K1-L1-30Thr-M1-Val-Gly-Ser-35Asn-Thr- Tyr-Z (SEQ ID NO:31) wherein A1 is Lys, Ala, Ser, Hydrogen or acetylated Lys; 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 Ser, Pro, Leu, Ile or Thr; L1 is Ser, Pro or Thr; M1 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 an amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, arlyoxy or aralkyloxy; provided that (a) when A1 is Lys, B1 is Ala, C1 is Val, D1 is His, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Phe, I1 is Ala, J1 is Ile, K1 is Ser, and M1 is Asn (SEQ ID NO:46); (b) when A1 is Lys, B1 is Ala, C1 is Ile, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Ala, J1 is Ile, K1 is Ser, L1 is Pro, and M1 is Asn (SEQ ID NO:47); (c) when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Thr, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Ala, J1 is Ile, K1 is Ser, L1 is Pro, and M1 is Asn (SEQ ID NO:48); (d) 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, K1 is Pro, L1 is Pro, and M1 is Asn (SEQ ID NO:41); (e) when 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 Pro, J1 is Val, K1 is Ser, L1 is Pro and M1 is Asn (SEQ ID NO:43); or (f) when A1 is Lys, B1 is Thr, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is His, H1 is Leu, I1 is Ala, J1 is Ala, K1 is Leu, L1 is Pro and M1 is Asp (SEQ ID NO:49); then one or more of any of A1 to M1 is not an L-amino acid and Z is not amino. 2. The method of calim 1 wherein the amylin agonist analogue has the following amino acid sequence: 1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1 20F1- G1—Asn-H1Gly-25Pro-I1-Leu-Pro-J1-30Thr-K1-Val-Gly-Ser-35Asn-Thr—Tyr-Z (SEQ ID NO:40) 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 thieother linkage; and Z is an 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, J1 is Pro, and K1 is Asn; then one or more 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. 3. The method of claim 1 wherein the amylin agonist analogue has 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 (SEQ ID NO:42) 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 disfulfide 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. 4. The method of claim 1 wherein the amylin agonist analogue has 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-30-Thr-K1-Val-Gly-Ser-35Asn-Thr-Tyr-Z (SEQ ID NO:44) where 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 (SEQ ID NO:41); 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. The method of claim 1 wherein the amylin agonist analogue has 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 (SEQ ID NO:45) 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 where are chemically bonded to each other to from 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 (SEQ ID NO:41); then one or more of A1 to J1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy. 6. The method of claim 1 wherein said amylin agonist analogue is any one of 18Arg25,28Pro—h-amylin (SEQ ID NO:3), des-1Lys18Arg25,28Pro-h-amylin (SEQ ID NO:6), 25,28,29Pro-h-amylin (SEQ ID NO:1), des-1Lys25,28,29Pro-h-amylin (SEQ ID NO:10), 18Arg25,28,29Pro-h-amylin (SEQ ID NO:8), des-1Lys18Arg25,28,29Pro-h-amylin (SEQ ID NO:9), 25Pro26Val28,29Pro-h-amylin (SEQ ID NO:7), or des-1Lys25Pro26Val28,29Pro-h-amylin (SEQ ID NO:38). 7. The method of claim 1 wherein the amylin agonist analogue is 25,28,29Pro-h-amylin (SEQ ID NO:1). 8. The method of claim 1 wherein the mammal has diabetes. 9. The method of claim 8 wherein the diabetes is type 1. 10. The method of claim 8 wherein the diabetes is type 2. 11. The method of claim 2 wherein the mammal has diabetes. 12. The method of claim 11 wherein the diabetes is type 1. 13. The method of claim 11 wherein the diabetes is type 2. 14. The method of claim 3 wherein the mammal has diabetes. 15. The method of claim 14 wherein the diabetes is type 1. 16. The method of claim 14 wherein the diabetes is type 2. 17. The method of claim 4 wherein the mammal has diabetes. 18. The method of claim 17 wherein the diabetes is type 1. 19. The method of claim 17 wherein the diabetes is type 2. 20. The method of claim 17 wherein the mammal has diabetes. 21. The method of claim 20 wherein the diabetes is type 1. 22. The method of claim 20 wherein the diabetets is type 2. 23. The method of claim 20 wherein the mammal has diabetes. 24. The method of claim 23 wherein the diabetes is type 1. 25. The method of claim 23 wherein the diabetes is type 2. 26. The method of claim 23 wherein the amylin agonist analogue has the following amino acid sequence: 1A1-X-Asn-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1- 20F1-G1Asn-H1-Gly-25I1-J1-Leu-K1-L1-30Thr-M1-Val-Gly-Ser-35Asn-Thr-Tyr-Z (SEQ ID NO:31) wherein A1 is Lys, Ala, Ser, Hydrogen or acetylated Lys; 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 Ser, Pro, Leu, Ile or Thr; L1 is Ser, Pro or Thr; M1 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 an amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that (a) when A1 is Lys, B1 is Ala, C1 is Val, D1 is His, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Phe, I1 is Ala, J1 is Ile, K1 is Ser, L1 is Ser, and M1 is Asn (SEQ ID NO:46); (b) when A1 is Lys, B1 is Ala, C1 is Ile, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, L1 is Ala, J1 is Ile, K1 is Ser, L1 is Pro, and M1 is Asn (SEQ ID NO:47); (c) when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Thr, F1 is Ser, G1 is Asn, H1 is Leu, L1 is Ala, J1 is Ile, K1 is Ser, L1 is Pro, and M1 is Asn (SEQ ID NO:48); (d) 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, K1 is Pro, L1 is Pro, and M1 is Asn (SEQ ID NO:41); (e) when 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 Pro, J1 is Val, K1 is Ser, L1 is Pro and M1 is Asn (SEQ ID NO:43); or (f) when A1 is Lys, B1 is Thr, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is His, H1 is Leu, I1 is Ala, J1 is Ala, K1 is Leu, L1 is Pro and M1 is Asp (SEQ ID NO:49); then one or more of any of A1 to M1 is not an L-amino acid and Z is not amino. 27. The method of claim 26 wherein the mammal has diabetes. 28. The method of claim 27 wherein the diabetes is type 1. 29. The method of claim 27 wherein the diabetes is type 2.