Thrombin receptor antagonists.

Abstract

Thrombin's proteolytically activated "tethered-ligand" receptor is widely expressed and mediates many of thrombin's actions on cells. Its central role in thrombin-stimulated human platelet activation and vascular smooth muscle proliferation as well as location in atherosclerotic plaques suggests receptor involvement in arterial thrombosis and atherosclerosis. Thrombin receptor antagonists, should they be effective, could be more selective than thrombin active site inhibitors in antithrombotic therapy as well as other indications. Blocking antibodies to peptides derived from the thrombin receptor have been used as prototypical thrombin receptor antagonists in vitro and have been useful in implicating this receptor in thrombin's actions on a variety of cell types. These antibodies have also shown the involvement of the receptor in arterial thrombosis models in nonhuman primates. Amino acid substitution studies have shown the structural requirements for receptor activation of peptides homologous to the new NH2-terminus. Peptide-based partial agonists and antagonists have been synthesized by NH2-terminal replacements of the serine in the receptor activating peptides. Current thrombin receptor antagonists lack potency and some are partial agonists; however, it is expected that more potent compounds will result from further investigation. The potency limitations are important to overcome before serious evaluation of their efficacy can be determined.