Pharmacological characterization of the active synthetic factor Xa inhibitors M55551 and M55165.

Factor Xa plays an important role in blood coagulation and is widely regarded as an attractive target for antithrombotic drug development. M55551 and M55165 (1-arylsulfonyl-3-piperazinone derivatives) are novel synthetic factor Xa inhibitors. In vitro, M55551 and M55165 competitively inhibited factor Xa with K(i) values of 3.2 nM and 2.3 nM, respectively, and prolonged clotting time in human and rat plasma. Pharmacokinetic analysis of these compounds revealed that M55551 was intravenously active with a short half-life (0.2 h) and that M55165 exhibited good bioavailability (31%) with a long half-life (3.9 h). Therefore, the antithrombotic effects of M55551 and M55165 were compared with those of the intravenous anticoagulant argatroban and the oral anticoagulant warfarin. Intravenous administration of M55551 and oral administration of M55165 inhibited thrombus formation at 0.3 mg/kg and 10 mg/kg, respectively, without significant prolongation of bleeding time. In contrast, although argatroban (0.3 mg/kg) and warfarin (1 mg/kg) also inhibited thrombus formation, significant prolongation of bleeding time was observed at dosages of 3 mg/kg and 1 mg/kg, respectively. These results suggest that M55551 and M55165 are potent factor Xa inhibitors that are active upon intravenous and oral administration, respectively, and that may prove clinically useful for the treatment of thrombosis while minimizing bleeding risks.