Mechanism of action and clinical development of platelet thrombin receptor antagonists.

Atherothrombotic disease is the leading cause of death worldwide. Currently, dual antiplatelet therapy with aspirin and ADP receptor antagonists has shown improved short- and long-term clinical outcomes but is associated with increased bleeding risk, and the rates of recurrent ischemic events still remain high. Selective inhibition of the principal protease-activated receptor (PAR)-1 for thrombin, the most potent platelet activator, represents a promising novel strategy to reduce ischemic events without increasing the risk of bleeding. Two PAR-1 antagonists are currently being tested in clinical trials: SCH 530348 and E5555. Both have demonstrated an antiplatelet effect without increasing bleeding time in preclinical trials. Results of Phase II trials showed that SCH 530348, in addition to standard antiplatelet therapy, was well tolerated and not associated with increased bleeding risk. The safety and tolerability of E5555 is being evaluated in patients with coronary artery disease and non-ST-segment elevation acute coronary syndrome in four Phase II clinical trials. Two large-scale Phase III trials assessing the efficacy of SCH 530348 in addition to the standard of care are currently ongoing. This article provides an overview of the current status of knowledge on platelet thrombin receptor antagonists, focusing on pharmacologic properties and clinical development.