Growth hormone secretatogue receptor antagonists and uses thereof
AssigneesThe Administrators of the Tulane Educational Fund, McGill University
InventorsCyril Y. Bowers, David H. Coy, Simon J. Hocart, Gloria S. Tannenbaum
Life of this patent
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Abstract
The present invention provides novel peptides that can modulate the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and sub-types, isoforms and variants thereof). These peptides are useful as antagonists of the ghrelin receptor as well as inverse agonist, partial agonist or a combination of these activities as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, diabetes, central nervous system disorders, genetic disorders, and hyperpro-liferative disorders.
Claims17
A synthetic peptide, wherein the peptide
- (i) comprises an amino acid sequence of formula (I):
- X1-Gly-Ser-X2-Phe-Leu-(X3)n-X4 (I) (SEQ ID NO:
- 4),
- wherein:
- X1 is Gly-Met-Ala-, Gly-DMet-Ala-, Ala-DMet-Ala-, Gly-Met-Alaψ[CH2NH]—, Ala-Met-Alaψ[CH2NH]—, Gly-DMet-Alaψ[CH2NH]—, Ala-DMet-Alaψ[CH2NH]—, Gly-Met-Ala[C(O)N(Me)]-, Ala-Met-Ala[C(O)N(Me)]-, Gly-DMet-Ala[C(O)N(Me)]-, Ala-DMet-Ala[C(O)N(Me)]-, Leu-Asp-Leu-Gly-Met-Ala-(SEQ ID NO:
- 6), Leu-Asp-Leu-Gly-DMet-Ala-, Leu-Asp-Leu-Ala-DMet-Ala-, Leu-Asp-Leu-Gly-Met-Alaψ[CH2NH]-(SEQ ID NO:
- 7), Leu-Asp-Leu-Ala-Met-Alaψ[CH2NH]-(SEQ ID NO:
- 8), Leu-Asp-Leu-Gly-DMet-Alaψ[CH2NH]—, Leu-Asp-Leu-Ala-DMet-Alaψ[CH2NH]—, Leu-Asp-Leu-Gly-Met-Ala[C(O)N(Me)]-(SEQ ID NO:
- 381), Leu-Asp-Leu-Ala-Met-Ala[C(O)N(Me)]-(SEQ ID NO:
- 382), Leu-Asp-Leu-Gly-DMet-Ala[C(O)N(Me)]-, or Leu-Asp-Leu-Ala-DMet-Ala[C(O)N(Me)]-;
- X2 is not a serine conjugated with a —C(O)C1-C20 alkyl group on the side chain OH of said serine, or X2 is a diaminopropionic acid conjugated with a —C(O)C1-C20 alkyl group on one of the amino groups of the diaminopropionic acid, or X2 is D- or L-tryptophan;
- each X3 is independently an amino acid;
- X4 is absent, NH2, or a carboxyl protecting group;
- amino acid residues of the dipeptide, tripeptide, tetrapeptide, pentapeptide, and hexapepetide are same or different and are selected from D amino acid, L amino acid, α-amino acid, β-amino acid, γ-amino acid, and γ-amino acid;
- n is an integer from 0 to 24;
- and
- pharmaceutically acceptable salts thereof;
- or
- (ii) consists of an amino acid sequence of formula (I):
- X1-Gly-Ser-X2-Phe-Leu-(X3)n—X4 (I) (SEQ ID NO:
- 4),
- wherein:
- X1 is Gly-Met-Ala-, Gly-DMet-Ala-, Ala-DMet-Ala-, Gly-Met-Alaψ[CH2NH]—, Ala-Met-Alaψ[CH2NH]—, Gly-DMet-Alaψ[CH2NH]—, Ala-DMet-Alaψ[CH2NH]—, Gly-Met-Ala[C(O)N(Me)]-, Ala-Met-Ala[C(O)N(Me)]-, Gly-DMet-Ala[C(O)N(Me)]-, Ala-DMet-Ala[C(O)N(Me)]-, Leu-Asp-Leu-Gly-Met-Ala-(SEQ ID NO:
- 6), Leu-Asp-Leu-Gly-DMet-Ala-, Leu-Asp-Leu-Ala-DMet-Ala-, Leu-Asp-Leu-Gly-Met-Alaψ[CH2NH]— (SEQ ID NO:
- 7), Leu-Asp-Leu-Ala-Met-Alaψ[CH2NH]— (SEQ ID NO:
- 8), Leu-Asp-Leu-Gly-DMet-Alaψ[CH2NH]—, Leu-Asp-Leu-Ala-DMet-Alaψ[CH7NH]—, Leu-Asp-Leu-Gly-Met-Ala[C(O)N(Me)]- (SEQ ID NO:
- 381), Leu-Asp-Leu-Ala-Met-Ala[C(O)N(Me)]- (SEQ ID NO:
- 382), Leu-Asp-Leu-Gly-DMet-Ala[C(O)N(Me)]-, or Leu-Asp-Leu-Ala-DMet-Ala[C(O)N(Me)]-;
- X2 is a serine conjugated with a —C(O)C1-C20 alkyl group on the side chain OH of said serine;
- each X3 is independently an amino acid;
- X4 is absent, NH2, or a carboxyl protecting group;
- n is an integer from 0 to 24;
- and
- pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.