Synthesis and evaluation of imidazole acetic acid inhibitors of activated thrombin-activatable fibrinolysis inhibitor as novel antithrombotics.

Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486, USA. james_barrow@merck.com

Journal of medicinal chemistry 2003 Dec 4

filter terms:

Thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator of fibrinolysis, and inhibitors of this enzyme have potential use in antithrombotic and thrombolytic therapy. Appropriately substituted imidazole acetic acids such as 10j were found to be potent inhibitors of activated TAFI and selective versus the related carboxypeptidases CPA, CPN, and CPM but not CPB. Further, 10j accelerated clot lysis in vitro and was shown to be efficacious in a primate model of thrombosis.

Citation

James C Barrow, Philippe G Nantermet, Shaun R Stauffer, Phung L Ngo, Melissa A Steinbeiser, Shi-Shan Mao, Steven S Carroll, Carolyn Bailey, Dennis Colussi, Michelle Bosserman, Christine Burlein, Jacquelynn J Cook, Gary Sitko, Philip R Tiller, Cynthia M Miller-Stein, Mark Rose, Daniel R McMasters, Joseph P Vacca, Harold G Selnick. Synthesis and evaluation of imidazole acetic acid inhibitors of activated thrombin-activatable fibrinolysis inhibitor as novel antithrombotics. Journal of medicinal chemistry. 2003 Dec 4;46(25):5294-7