Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis

PAR4
is a promising antithrombotic target with potential for separation
of efficacy from bleeding risk relative to current antiplatelet therapies.
In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based
HTS hit 3 with low μM potency was identified. Optimization
of the HTS hit through the use of positional SAR scanning and the
design of conformationally constrained cores led to the discovery
of a quinoxaline-benzothiazole series as potent and selective PAR4
antagonists. The lead compound 48, possessing a 2 nM
IC50 against PAR4 activation by γ-thrombin in platelet-rich
plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated
robust antithrombotic efficacy and minimal bleeding in the cynomolgus
monkey models.