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