In vitro studies of a new synthetic thrombin inhibitor

(2R, 4R)4-methyl-1-[N alpha-(3-methyl-1,2,3,4-tetrahydro-8-quinoline- sulfonyl)-L-arginyl]-2-piperidine carboxylic acid monohydrate (MCI-9038) was found to be a potent synthetic inhibitor of thrombin. In concentrations as low as 1 microM, the thrombin time, prothrombin time, and partial thromboplastin time were more than doubled. The venom (Bothrops atrox) time was similarly prolonged. The drug also inhibited the thrombin-induced activation of factors VIII and XIII. While MCI-9038 in concentrations of 10(-4) M had no effect on platelet aggregation induced by collagen, ADP, epinephrine, and arachidonate, nanomolar concentrations inhibited thrombin-induced platelet aggregation and the release of platelet ADP. The drug also significantly inhibited the adhesion of thrombin-treated platelets to cultured bovine aortic endothelial cells. We conclude that MCI-9038 is an extremely potent inhibitor of the effects of thrombin on platelets and clotting factors.