Publication — IRIC

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

In an effort to identify novel antithrombotics, we have investigated 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 SAR 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.

Date de publication
27 juin 2019
Chercheurs
Miller MM, Banville J, Friends T, Gagnon M, Hangeland JJ, Lavalee JF, Martel A, O'Grady H, Remillard R, Ruediger EH, Tremblay F, Posy S, Allegretto N, Guarino VR, Harden D, Harper TW, Hartl K, Josephs J, Malmstrom S, Watson CA, Yang Y, Zhang G, Wong PC, Yang J, Bouvier M, Seiffert DA, Wexler RR, Lawrence RM, Priestley ES, Marinier A
Référence PubMed
J. Med. Chem. 2019
ID PubMed
31246024