Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy.
Michael M MillerJacques BanvilleTodd J FriendsMark GagnonJon J HangelandJean-François LavalléeAlain MartelHarold O'GradyRoger RémillardEdward RuedigerFrançois TremblayShana L PosyNick J AllegrettoVictor R GuarinoDavid G HardenTimothy W HarperKaren HartlJonathan JosephsSarah MalmstromCarol WatsonYanou YangGe ZhangPancras WongJing YangMichel BouvierDietmar A SeiffertRuth R WexlerR Michael LawrenceE Scott PriestleyAnne MarinierPublished in: Journal of medicinal chemistry (2019)
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.