Molecular design and structure-activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.

Abstract A series of structurally novel small molecule inhibitors of human α-thrombin was prepared to elucidate their structure–activity relationships (SARs), selectivity and activity in vivo. BMS-189664 ( 3 ) is identified as a potent, selective, and orally active reversible inhibitor of human α-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.