Cyclic peptides as g-protein-coupled receptor antagonists
AssigneePromics Pty Limited
InventorsStephen Maxwell, Ian Alexander, David Fairlie, Darren March, Michael Whitehouse
Life of this patent
Estimating the term…
Abstract
The invention relates to novel cyclic compounds which have the ability to modulate the activity of G protein-coupled receptors. The compounds preferably act as antagonists. In preferred embodiments, the invention provides cyclic peptidic and peptidomimetic antagonists of C5a receptors, which are active against C5a receptors on polymorphonuclear leukocytes and macrophages. The compounds of the invention are both potent and selective, and are useful in the treatment of a variety of inflammatory conditions.
Claims18
A compound which is an antagonist of a G protein-coupled receptor, which has substantially no agonist activity, and which is a cyclic peptide or peptidomimetic of general formula
- where A is H, alkyl, aryl, NH2, NH-alkyl, N(alkyl)2, NH-aryl, NH-acyl, NH-benzoyl, NHSO3, NHSO2-alkyl, NHSO2-aryl, OH, O-alkyl, or O-aryl;
- B is an alkyl, aryl, benzyl, naphthyl or indole group, or is the side chain of L-phenylalanine or L-phenylglycine;
- C is the side chain of glycine, alanine, leucine, valine, proline, hydroxyproline, or thioproline;
- D is the side chain of D-Leucine, D-homoleucine, D-cyclohexylalanine, D-homocyclohexylalanine, D-valine, D-norleucine, D-homo-norleucine, D-phenylalanine, D-tetrahydroisoquinoline, D-glutamine, D-glutamate, or D-tyrosine;
- E is L-1-napthyl or L-3-benzothienyl alanine, or is the side chain of an amino acid selected from the group consisting of L-phenylalanine, L-tryptophan and L-homotryptophan;
- F is the side chain of L-arginine, L-homoarginine, L-citrulline, or L-canavanine, or a bioisostere thereof;
- X is —(CH2)nNH— or (CH2)n—S—, where n is an integer of from 1 to 4;
- —(CH2)2O—;
- —(CH2)3O—;
- —(CH2)3—;
- —(CH2)4—;
- —CH2COCHRNH—;
- or —CH2—CHCOCHRNH—, and where R is the side chain of any common or uncommon amino acid,
- with the proviso that the compound is not AcF-[OPdChaWR] (compound 1).
Dependencies are inferred from the claim text.