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Thrombin Receptor Antagonists, Recent Advances in PAR-1 Antagonist Development

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The receptor for the serine protease thrombin, the protease-activated receptor-1 (PAR-1), has been recently characterized. Its key roles in thrombin-stimulated human platelet activation, vascular endothelial and smooth muscle proliferation, inflammatory responses and neurodegeneration suggest receptor involvement in various disorders such as arterial thrombosis, atherosclerosis, restenosis, inflammation and myocardial infarction. It has been established that thrombin elicits the majority of its effects via PAR-1. PAR-1 has a novel mechanism of activation. The receptor, a member of the seven-transmembrane domain receptor family, is cleaved by thrombin at a specific site on the N-terminal extension, and a newly exposed N-terminus acts as a “tethered ligand” to activate the receptor itself. The need for development of a PAR-1 antagonist that may be valuable as a therapeutic agent has been recognized. An intriguing challenge is the necessity of the antagonist to compete with an intramolecular ligand while showing no intrinsic activity. The lead compounds were found to be synthetic peptides containing N-terminal hexapeptide or pentapeptide (Ser-Phe-Leu-Leu-Arg- Asn, Ser-Phe-Leu-Leu-Arg) or modified sequences (TRAPs thrombin receptor-activating peptides), which exhibit full PAR-1 agonist activity. Selective PAR-1 antagonists have already been synthesized. Though their potency is still not enough to justify therapeutic use, it is clear that future progress will bring a novel class of drugs-thrombin receptor antagonists. The emphasis of this review, therefore, will be placed on advances in the discovery of potent and selective PAR-1 antagonists.

Keywords: par-1 antagonist; protease-activated receptor-1; tethered ligand; thrombin receptor; thrombin receptor activating peptide

Document Type: Review Article


Publication date: July 1, 2002

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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