PAR4 antagonists have potential as a novel class of anti-platelet agents with improved efficacy/safety profile compared to current anti-platelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a high-throughput screening (HTS) campaign yielded a quinoxaline hit with low uM potency. Optimization of the HTS hit by positional SAR scanning and design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonist. The lead compound, possessing a 2 nM IC<sub>50</sub> against PAR4 activation by g-thrombin and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.

Discovery of potent and selective quinoxaline-based protease-activated receptor 4 (PAR4) antagonists for the prevention of arterial thrombosis

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.