Back to results
US 7,407,934 B2Granted
Methods for regulating postprandial blood glucose
AssigneeAmylin Pharmaceuticals, Inc.
InventorsOrville G. Kolterman, Andrew A. Young, Timothy J. Rink, Kathleen Ann Keating Brown
Life of this patent
Estimating the term…
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.
Claims29
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.
83 more elements
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-E120F1- 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.
13 more elements
Dependencies are inferred from the claim text.