Thrombin receptor antagonists as novel therapeutic targets

In addition to its pivotal role in hemostasis, thrombin activates various cell types such as platelets and vascular smooth muscle cells via proteolytic processing of specific cell-surface receptors known as proteinase activated receptors (PARs), the prototype of which is PAR-1. Thrombin receptor activation is likely to play a key role in cardiovascular disorders such as arterial thrombosis, atherosclerosis and restenosis, and as such a thrombin receptor antagonist should have potential utility in the treatment of these disorders. Since the fibrin pathway is unaffected by thrombin receptor antagonism, a thrombin receptor antagonist is expected to have minimal bleeding liability, which is a complicating factor in existing antithrombotic therapy. The currently available collection of thrombin receptor antagonists fall into three categories: (i) peptide antagonists; (ii) peptidomimetics; and (iii) non-peptide thrombin receptor antagonists, and this review outlines the development of members of these classes.