1区 · 医学
Article
作者: Lavallée, Jean-François ; Hangeland, Jon J. ; Gagnon, Mark ; Hartl, Karen ; Allegretto, Nick J. ; Yang, Jing ; Posy, Shana L. ; Lawrence, R. Michael ; Josephs, Jonathan ; Seiffert, Dietmar A. ; Guarino, Victor R. ; Harper, Timothy W. ; Wong, Pancras ; Friends, Todd J. ; Yang, Yanou ; Bouvier, Michel ; Wexler, Ruth R. ; Malmstrom, Sarah ; Rémillard, Roger ; Tremblay, François ; Marinier, Anne ; O’Grady, Harold ; Miller, Michael M. ; Harden, David G. ; Martel, Alain ; Zhang, Ge ; Watson, Carol ; Priestley, E. Scott ; Ruediger, Edward ; Banville, Jacques
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.
