Challenges in Design and Development of PAR Inhibitors

Abstract SCI-45

Inappropriate and sustained activation of platelets is a major cause of vascular occlusive diseases such as angina, myocardial infarction, and stroke. The development of thrombi within blood vessels results from the formation of platelet aggregates and fibrin deposits, and heavily depends on the actions of α-thrombin. It is now well recognized that human platelet responses to α-thrombin are mediated by the protease-activated receptors PAR1 and PAR4. Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G-protein-coupled receptors, which are enzymatically cleaved to expose a new extracellular N-terminus that acts as a “tethered” activating ligand. Since the discovery of PAR1 as the major contributor to human platelet aggregation, there has been a keen interest to develop antagonist as potential antithrombotics. However, there have been many issues and challenges in this endeavor. One crucial challenge to the discovery of potent antagonists is the strong entropy advantage offered by the intramolecular binding mechanism of PARs activation, which presents a great disadvantage to a circulating small molecule antagonist. To be an effective therapeutic agent, a PAR1 antagonist not only should bind tightly to the receptor but also possess suitable binding kinetics. Another issue for the discovery of PAR1 antagonists is the preclinical logistics associated with species variability of PAR1 on platelets. Despite these challenges, PAR1 has been an attractive drug target and there has been considerable activity and progress in the discovery and development of PAR1 antagonist as therapeutic agents. The promise of these novel therapeutics is reflected by two antiplatelet PAR1 antagonists in advanced clinical trials. The clinical benefits derived from these agents will be determined by the tight balance between delivering efficacy in the context of thrombotic disease and controlling the bleeding risk. The discussion will focus on the challenges from discovery to development of these great potential opportunities in the prevention of atherothrombotic disease.