Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy

In
an effort to identify novel antithrombotics, we have investigated
protease-activated receptor 4 (PAR4) antagonism by developing and
evaluating a tool compound, UDM-001651, in a monkey thrombosis
model. Beginning with a high-throughput screening hit, we identified
an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure–activity
relationship studies enabled optimization to a potent, selective,
and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and
shown to have robust antithrombotic efficacy and no prolongation of
kidney bleeding time. This combination of excellent efficacy and safety
margin strongly validates PAR4 antagonism as a promising antithrombotic
mechanism.