PAR-1 inhibitors

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Editors-In-Chief: Sergio Leonardi, M.D., Duke Clinical Research Institute; C. Michael Gibson, M.S., M.D.

Overview

Protease Activated Receptor (PAR)-1 inhibitors (also known as thrombin receptor antagonists, TRAs) are a new class of antiplatelet agents that antagonize platelet activation mediated by thrombin, the most potent platelet activator.

The cellular actions of thrombin (including the activation of platelets) are mediated by a 7-domain receptor named PAR. The 2 main platelet PAR receptors in humans are PAR-1 and PAR-4, with the former being the principal thrombin receptor. Thrombin cleaves one peptide bond (Arg41-Ser42) of the receptor extracellular domain exposing a new N-terminus, which is called “tethered ligand”. This tethered ligand is the resident agonist of the PARs that ultimately causes its activation. PAR-1 inhibitors selectively block the interaction of the tethered ligand with the activation site, ultimately preventing PAR-1 activation. The 2 agents in most advanced clinical development are vorapaxar (previously known as SCH530348) and atopaxar (previously known as E-5555).