Thrombin receptor modulators: Medicinal chemistry, biological evaluation, and clinical application

Abstract

The serine protease a-thrombin maintains haemostasis through its coagulant, anticoagulant, and platelet-activator functions. This enzyme also has important cellular effects involving cell proliferation, cytokine and growth factor release, and tissue remodeling, which are mediated by G-protein coupled receptors known as protease-activated receptors (PARs). Thrombin can activate three of the four PAR family members, and PAR1 is the primary thrombin-responsive receptor in human cells. PAR1 plays an important role during the response to tissue injury and the associated inflammatory processes. The blockade of PAR1 offers a new approach for treating various disorders that depend on thrombin generation, including thrombosis and restenosis. Antagonists of PAR1 will interrupt thrombin's receptor function, but not thrombin's proteolytic activity, thereby providing an alternative means to attenuate the pathological effects of thrombin. This chapter deals with the topic of PAR1, with the key medicinal chemistry, pharmacology, and clinical aspects of PAR1 antagonists, and with the topic of PAR4. The full potential of PAR1 antagonists has yet to be realized commercially, but the promise of novel therapeutics is reflected by two antiplatelet PAR1 antagonists in advanced human clinical trials.