US2004192608A1PendingUtilityA1
Treatment of obesity
Est. expirySep 8, 2017(expired)· nominal 20-yr term from priority
A61K 38/00C07K 14/61A61P 3/04A61P 5/06A61P 43/00
56
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Claims
Abstract
A method for the treatment of obesity in an animal such as a human, comprises administering to the animal an effective amount of a peptide which comprises an analogue of the carboxyl-terminal sequence of a growth hormone, particularly an analogue of the carboxyl-terminal sequence of human growth hormone containing amino acid residues 177-191. A pharmaceutical composition for use in the treatment of obesity is also disclosed.
Claims
exact text as granted — not AI-modified1 . A method for the treatment of obesity in an animal, said method comprising administering to the animal an effective amount of
(A) a peptide comprising an analogue of the carboxyl-terminal sequence of a growth hormone, said caxboxyl-terminal sequence containing amino acid residues 177-191 of human growth hormone: Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val- (SEQ ID NO: 1) Glu-Gly-Ser-Cys-Gly-Phe, or a corresponding sequence of a non-human mammalian growth hormone; wherein in said analogue
(i) amino acids at positions 182 and 189 of hGH are joined by a bond to promote a cyclic conformation, and/or
(ii) amino acids at positions 183 and 186 of hGH are joined by a salt bridge or a covalent bond;
(B) or an organic or inorganic acid addition salt thereof.
2 . The method of claim 1 , wherein said peptide comprises a bond between amino acids at positions 182 and 189 which is a disulfide bond.
3 . The method of claim 1 , wherein said peptide comprises amino acids at positions 182 and 189 selected from the group consisting of L-Cys, D-Cys, L-Pen and D-Pen.
4 . The method of claim 1 , wherein said peptide comprises amino acids at positions 183 and 186 which are joined by an amide covalent bond.
5 . The method of claim 4 , wherein said peptide comprises amino acids at positions 183 and 186 which axe (X and Y) or (Y and X), respectively, where:
X is selected from the group consisting of L- or D-Lys or Om and Y is selected from the group consisting of L- or D- Asp and Glu.
6 . A method for the treatment of obesity in an animal, said method comprising administering to the animal an effective amount of
(A) a peptide of the sequence: X 1 m-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser- (SEQ ID NO: 2) Val-Glu-Gly-Ser-Cys-Gly-Phe-X 2 n wherein X 1 and X 2 are each selected from the group consisting of L- or D- Arg, His, Lys and Tyr, and m and n are each 0, 1, 2, or 3 with the proviso that at least m or n is 1; (B) or a cyclic disulfide thereof or an organic or inorganic acid addition salt thereof.
7 . A method for the treatment of obesity in an animal, said method comprising administering to the animal an effective amount of
(A) a peptide of the sequence: Y 1 -Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser- (SEQ ID NO: 3) Val-Glu-Gly-Ser-Cys-Gly-Phe wherein Y 1 is selected from the group consisting of the desamino form (H), acetyl (CH 3 CO—) and other acyl groups; or (B) a cyclic disulfide thereof or an organic or inorganic acid addition salt thereof.
8 . A method for the treatment of obesity in an animal, said method comprising administering to the animal an effective amount of
(A) a peptide of the sequence: Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe-Y 2 (SEQ ID NO: 4) wherein Y 2 is selected from the group consisting of CONH 2 and alkyl amide groups; or (B) a cyclic disulfide thereof or an organic or inorganic acid addition salt thereof.
9 . A method for the treatment of obesity in an animal, said method comprising administering to the animal an effective amount of a peptide selected from the group consisting of:
Ref No.
STRUCTURE
9502
Leu Arg Ile Val Gln Pen Arg Ser Val Glu Gly Ser Pen Gly Phe
9405
CH 3 CO - Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9410
H - Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9404
Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe - CONH 2
9407
Leu Arg Ile Val Gln Cys Lys Ser Val Gln Gly Ser Cys Gly Phe
9408
Leu Arg Ile Val Gln Cys Lys Ser Val Glu Gly Ser Cys Gly Phe
| |(amide bond)
9604
Tyr Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9605
Lys Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9618
Lys Lys Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9607
Ala Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9606
Leu Lys Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9608
Leu Arg Ala Val Gln Cys Arg Ser Val Gln Gly Ser Cys Gly Phe
9403
Leu Arg Lys Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9609
Leu Arg Ile Ala Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9610
Leu Arg Ile Val Ala Cys Arg Ser Val Glu Gly Ser Cys Gly Phe
9612
Leu Arg Ile Val Gln Cys Arg Ala Val Glu Gly Ser Cys Gly Phe
9613
Leu Arg Ile Val Gln Cys Arg Ser Ala Glu Gly Ser Cys Gly Phe
9615
Leu Arg Ile Val Gln Cys Arg Ser Val Glu Ala Ser Cys Gly Phe
9616
Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ala Cys Gly Phe
9602
Leu Arg Ile Val Gln Cys Arg Ser Val Flu Gly Ser Cys Ala Phe
9501
Leu Arg Ile Val Gln Cys Arg Ser Val Glu D-Ala Ser Cys D-Ala Phe
9601
Leu Arg Ile Val Gln Cys Arg Ser Val Glu Gly Ser Cys Gly Ala
wherein the amino acid residue abbreviations used are in accordance with the standard peptide nomenclature:
Gly = Glycine;
Ile = Isoleucine;
Glu = Glutamic Acid;
Phe = Phenylalanine;
Cys = Cysteine
Arg = Arginine;
Gln = Glutamine;
Leu = Leucine;
Ser = Serine;
Val = Valine;
Lys = Lysine;
Ala = Alanine;
Asp = Aspartic acid;
His = Histidine;
Orn = Ornithine;
Tyr = Tyrosine;
Pen = Penicillamine
(β,β′-/Dimethyl-Cysteine)
wherein all amino acids, except for glycine, are of the L-absolute configuration, unless indicated as D-absolute configuration, and the peptide has a cyclic disulfide bond between Cys(192) and Cys(189) or Pen(182) and Pen(189) as appropriate;
or an organic or inorganic acid addition salt thereof.
10 . The method of claim 9 wherein said peptide comprises amino acids at positions 183 and 186 which are joined by a salt bridge, and are (X and Y) or (Y and X), respectively, where:
X is a positively charged amino acid, and
Y is a negatively charged amino acid.
11 . The method of claim 10 wherein X is selected from the group consisting of L- or D-Arg, Lys or Om, and Y is selected from the group consisting of L- or D- Asp or Glu.
12 . The method of claim 1 wherein the animal is a human.
13 . The method of claim 1 wherein the peptide is administered orally.
14 . A peptide which comprises an analogue of the carboxyl-terminal sequence of a growth hormone, said carboxyl-terminal sequence containing
(A) amino acid residues 177-191 of human growth hormone; Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val- (SEQ ID NO: 1) Glu-Gly-Ser-Cys-Gly-Phe, or (B) a corresponding sequence of a non-human mammalian growth hormone; wherein in said analogue
(i) amino acids at positions 182 and 189 of hGH are joined by a bond to promote a cyclic conformation; and/or
(ii) amino acids at positions 183 and 186 of hGH are joined by a salt bridge or a covalent bond;
or an organic or inorganic acid addition salt thereof.
15 . The peptide of claim 14 , wherein the bond between amino acids at positions 182 and 189 is a disulfide bond.
16 . The peptide of claim 14 , wherein the amino acids at positions 182 and 189 are selected from the group consisting of L-Cys, D-Cys, L-Pen and D-Pen.
17 . The peptide of claim 14 , wherein the amino acids at positions 183 and 186 are joined by a salt bridge, and are (X and Y) or (Y and X), respectively, where:
X is a positively charged amino acid, and Y is a negatively charged amino acid.
18 . The peptide of claim 17 , wherein X is selected from the group consisting of L- or D-Arg, Lys or Om, and Y is selected from the group consisting of L- or D- Asp or Glu.
19 . The peptide of claim 14 , wherein the amino acids at positions 183 and 186 are joined by an amide covalent bond.
20 . The peptide of claim 19 , wherein the amino acids at positions 183 and 186 are (X and Y) or (Y and X), respectively, where:
X is selected from the group consisting of L- or D- Lys or Orn, and Y is selected from the group consisting of L- or D- Asp and Glu.
21 . A peptide of the sequence:
Y 1 -Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-
(SEQ ID NO: 3)
Val-Glu-Gly-Ser-Cys-Gly-Phe
wherein Y 1 is selected from the group consisting of the desamino form (H), acetyl (CH 3 CO—) and other acyl groups;
or a cyclic disulfide thereof or an organic or inorganic acid addition salt thereof.
22 . A peptide of the sequence:
Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe-Y 2
(SEQ ID NO:4)
wherein Y 2 is selected from the group consisting of CONH 2 and alkyl amide groups;
or a cyclic disulfide thereof or an organic or inorganic acid addition salt thereof.
23 . A pharmaceutical composition for use in the treatment of obesity in an animal, which comprises an effective amount of the peptide of claim 14 , together with one or more pharmaceutically acceptable carriers and/or diluents
24 . A peptide analogue of amino acid residues 177-191 of human growth hormone, of the formula;
X 0 -X 1 -X 2 -Arg-X 3 -X 4 -X 5 -Cys-Arg-X 6 -X 7 -Glu-X 8 -X 9 -Cys-X 10 -X 11 -X 12
wherein X 0 is des-X 0 or any number of one to ten amino acids; X 1 is des-X 1 or any amino acid, X 2 is des-X 2 or any amino acid; X 3 is des-X 3 or any number of one to three amino acids, X 4 is any amino acid; X 5 is any amino acid; X 6 is des-X 6 or any number of one to three amino acids; X 7 is any amino acid; X 8 is des-X 8 or any number of one to three amino acids; X 9 is any amino acid; X 10 is any amino acid; X 11 is any amino acid; X 12 is des-X 12 , or any number of one to ten amino acids, but excludes hGH177-191, hGH176-191 and hGH172-191.
25 . The peptide analogue of claim 24 wherein X 0 is des-X 0 or Lys; X 1 is des-X 1 , CH 3 CO, H, Tyr, or Lys; X 2 is Leu or Ala; X 3 is Ile, Lys, or Ala; X 4 is Val or Ala; X 5 is Gln or Ala; X 6 is Ser or Ala; X 7 is Val or Ala; X 8 is Gly, Ala, or D-Ala; X 9 is Ser or Ala; X 10 Gly, Ala, or D-Ala; X 11 is Phe or Ala; X 12 is des-X 12 , or any amino acid.
26 . A peptide analogue of amino acid residues 177-191 of human growth hormone, of the formula;
27 . The peptide analogue of 26 wherein X 0 is des-X 0 or Lys; X 1 is des-X 1 , CH 3 CO, H, Tyr, or Lys; X 2 is Leu or Ala; X 3 is Ile, Lys, or Ala; X 4 is Val or Ala; X 5 is Gln or Ala; X 6 is Ser or Ala; X 7 is Val or Ala; X 8 is Gly, Ala, or D-Ala; X 9 is Ser or Ala; X 10 Gly, Ala, or D-Ala; X 11 is Phe or Ala; X 12 is des-X 12 , or any amino acid.
28 . A peptide analogue of amino acid residues 177-191 of human growth hormone, of the formula;
X 0 -X 1 -X 2 -Lys-X 3 -X 4 -X 5 -Cys-Arg-X 6 -X 7 -Glu-X 8 -X 9 -Cys-X 10 -X 11 -X 12
wherein X 0 is des-X 0 or any number of one to ten amino acids; X 1 is des-X 1 or any amino acid, X 2 is des-X 2 or any amino acid; X 3 is des-X 3 or any number of one to three amino acids, X 4 is any amino acid; X 5 is any amino acid; X 6 is des-X 6 or any number of one to three amino acids; X 7 is any amino acid; X 8 is des-X 8 or any number of one to three amino acids; X 9 is any amino acid; X 10 is any amino acid; X 11 is any amino acid; X 12 is des-X 12 , or any number of one to ten amino acids, but excludes hGH177-191, hGHI76-191 and hGH172-191.
29 . The peptide analogue of claim 28 wherein X 0 is des-X 0 or Lys; X 1 is des-X 1 , CH 3 CO, H, Tyr, or Lys; X 2 is Leu or Ala; X 3 is Ile, Lys, or Ala; X 4 is Val or Ala; X 5 is Gln or Ala; X 6 is Ser or Ala; X 7 is Val or Ala; X 8 is Gly, Ala, or D-Ala; X 9 is Ser or Ala; X 10 Gly, Ala, or D-Ala; X 11 is Phe or Ala; X 12 is des-X 12 , or any amino acid.
30 . A peptide analogue of amino acid residues 177-191 of human growth hormone, of the formula;
X 0 -X 1 -X 2 -Arg-X 3 -X 4 -X 5 -Cys-Lys-X 6 -X 7 -Glu-X 8 -X 9 -Cys-X 10 -X 11 -X 12
wherein X 0 is des-X 0 or any number of one to ten amino acids; X 1 is des-X 1 or any amino acid, X 2 is des-X 2 or any amino acid; X 3 is des-X 3 or any number of one to three amino acids, X 4 is any amino acid; X 5 is any amino acid; X 6 is des-X 6 or any number of one to three amino acids; X 7 is any amino acid; X 8 is des-X 8 or any number of one to three amino acids; X 9 is any amino acid; X 10 is any amino acid; X 11 is any amino acid; X 12 is des-X 12 , or any number of one to ten amino acids, but excludes hGH177-191, hGH176-191 and hGH172-191.
31 . The peptide analogue of claim 30 wherein X 0 is des-X 0 or Lys; X 1 is des-X 1 , CH 3 CO, H, Tyr, or Lys; X 2 is Leu or Ala; X 3 is Ile, Lys, or Ala; X 4 is Val or Ala; X 5 is Gln or Ala; X 6 is Ser or Ala; X 7 is Val or Ala; X 8 is Gly, Ala, or D-Ala; X 9 is Ser or Ala; X 10 Gly, Ala, or D-Ala; X 11 is Phe or Ala; X 12 is des-X 12 , or any amino acid.Cited by (0)
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