Thrombin receptors and their antagonists: an update on the patent literature

Protease-activated receptors (PARs) are a family of G-protein-coupled receptors. Of the four members so far identified PAR-1, PAR-3 and PAR-4 are thrombin receptors. PAR-1 has been shown to be involved in mediating platelet aggregation, cell proliferation, inflammatory responses and neurodegeneration. Early attempts to develop PAR-1 antagonists failed because of problems of poor efficacy, possibly due to the tethered ligand intramolecular binding following enzymatic receptor cleavage. PAR-1 antagonists, so far developed, can be chemically classified into two major groups: i) peptide/peptidomimetic antagonists; ii) non-peptide based antagonists. Two PAR-1 antagonists, SCH-530348 from Schering-Plough and E-5555 from Eisai Company, are in clinical trials for the prevention of arterial thrombosis.