Methods for regulating gastrointestinal motility
AssigneeAmylin Pharmaceuticals, Inc.
InventorsOrville G. Kolterman, Andrew A. Young, Timothy J. Rink, Kathleen Ann Keating Brown
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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.
Claims22
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.
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.
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.
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.
Dependencies are inferred from the claim text.