Amylin agonist peptides and uses therefor
AssigneeAmylin Pharmaceuticals, Inc.
InventorsLaura S. L. Gaeta, Howard Jones, Elisabeth Albrecht
Life of this patent
Estimating the term…
Abstract
Agonist analogues of amylin and related pharmaceutical compositions, and methods of treatment of diabetes and other insulin-requiring states, as well as methods of treatment of hypoglycemia, are provided.
Claims45
An agonist analogue of amylin having the amino acid sequence:
- ##STR1## 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 or Thr;
- K.sub.1 is Asn, Asp or Gln;
- X and Y are independently selected amino acid residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage is 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, J.sub.1 is Pro, 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.
An agonist analogue of amylin having the amino acid sequence:
- ##STR2## 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 is Asn, Asp or Gln;
- X and Y are independently selected amino acid residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage is 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.
An agonist analogue of amylin having the amino acid sequence:
- ##STR3## 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 amino acid residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage is 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 aralkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.
An agonist analogue of amylin having the amino acid sequence:
- ##STR4## 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 Asn, Asp or Gln;
- X and Y are independently selected amino acid residues having side chains which are chemically bonded to each other to form an intramolecular linkage wherein said intramolecular linkage is 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.
.sup.18 Arg.sup.25,28 Pro-h-amylin.
des-.sup.1 Lys.sup.18 Arg.sup.25,28 Pro-h-amylin.
.sup.25,28,29 Pro-h-amylin.
des-.sup.1 Lys.sup.25,28,29 Pro-h-amylin.
.sup.18 Arg.sup.25,28,29 Pro-h-amylin.
des-.sup.1 Lys.sup.18 Arg.sup.25,28,29 Pro-h-amylin.
.sup.25 Pro.sup.26 Val.sup.28,29 Pro-h-amylin.
A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of .sup.25,28,29 Pro-h-amylin.
A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of .sup.25,28,29 Pro-h-amylin and a therapeutically effective amount of an insulin.
A composition comprising a therapeutically effective amount of .sup.25,28,29 Pro-h-amylin in a pharmaceutically acceptable carrier.
A composition comprising a therapeutically effective amount of .sup.25,28,29 Pro-h-amylin and an insulin admixed in a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.