Amylin agonist peptides and uses therefor
First Claim
Patent Images
1. An agonist analogue of amylin having the amino acid sequence:
- ##STR1## 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 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 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 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.
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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.
83 Citations
45 Claims
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1. An agonist analogue of amylin having the amino acid sequence:
- ##STR1## 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 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 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 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. - View Dependent Claims (2, 3, 13, 14, 16, 24, 25, 26, 30, 36, 38)
- ##STR1## wherein A1 is Lys, Ala, Ser or hydrogen;
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4. An agonist analogue of amylin having the amino acid sequence:
- ##STR2## 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 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) 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. - View Dependent Claims (5, 6, 31, 39)
- ##STR2## wherein A1 is Lys, Ala, Ser or hydrogen;
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7. An agonist analogue of amylin having the amino acid sequence:
- ##STR3## 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 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 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 aralkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy. - View Dependent Claims (8, 9, 15, 32, 40)
- ##STR3## wherein A1 is Lys, Ala, Ser or hydrogen;
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10. An agonist analogue of amylin having the amino acid sequence:
- ##STR4## 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 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 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. - View Dependent Claims (11, 12, 33, 41, 44)
- ##STR4## wherein A1 is Lys, Ala, Ser or hydrogen;
- 17. 18 Arg25,28 Pro-h-amylin.
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18. des-1 Lys18 Arg25,28 Pro-h-amylin.
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19. 25,28,29 Pro-h-amylin.
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20. des-1 Lys25,28,29 Pro-h-amylin.
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21. 18 Arg25,28,29 Pro-h-amylin.
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22. des-1 Lys18 Arg25,28,29 Pro-h-amylin.
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23. 25 Pro26 Val28,29 Pro-h-amylin.
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35. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of 25,28,29 Pro-h-amylin.
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37. A method for the treatment of diabetes mellitus in a mammal comprising the administration to said mammal of a therapeutically effective amount of 25,28,29 Pro-h-amylin and a therapeutically effective amount of an insulin.
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43. A composition comprising a therapeutically effective amount of 25,28,29 Pro-h-amylin in a pharmaceutically acceptable carrier.
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45. A composition comprising a therapeutically effective amount of 25,28,29 Pro-h-amylin and an insulin admixed in a pharmaceutically acceptable carrier.
Specification