Thrombin receptor (PAR-1) antagonists as novel antithrombotic agents

Abstract

In addition to its central role in haemostasis and wound healing, thrombin activates platelets and smooth muscle cells by proteolytic activation of cell surface protease-activated receptor-1 (PAR-1), which is also known as the thrombin receptor. Thrombin is the most potent activator of human platelets and, as such, a thrombin receptor antagonist is likely to exert potent antithrombotic effect in platelet-rich arterial thrombosis. As thrombin receptor antagonism does not inhibit the ability of thrombin to generate fibrin, such an agent is likely to have less bleeding liability than conventional anticoagulants. The proof-of-concept of the antithrombotic effect of PAR-1 antagonists has been established in several non-human primate models. The current success of PAR-1 research is underscored by the advancement of two candidates into clinical trails for acute coronary syndrome by Schering-Plough and Eisai Company.