Factor Xa Inhibitors

Thrombin occupies a central position in thrombus formation and eventually has been a target to develop anticoagulant agents. Although both heparin and warfarin have been used as anticoagulants, a more useful, ideal anticoagulant is desired at bedside. Numerous efforts to develop a direct inhibitor of thrombin led to the discovery of improved anticoagulants including argatoroban. However, no orally available agent has been developed yet. FXa is responsible for prothrombin activation to generate thrombin and provides an alternative strategy to inhibit the coagulation cascade. In contrast with ATIII-dependent type FXa inhibitor, direct ATIII­ independent type inhibitors, such as tick anticoagulant peptide and antistasin, showed an inhibitory effect on arterial as well as venous thrombosis models, which was comparable to the effects of thrombin direct inhibitors or glycoprotein llb/Illa inhibitors. We synthesized a low molecular weight, orally active FXa inhibitor, DX- 9065l!, which also showed antithrombotic effect in various kind of thrombosis models. Further, FXa inhibitors have been known to have unique characteristics preferable to those of thrombin inhibitors. In this article, we review the pharmacological profile and structure-activity relationships of FXa inhibitors, ranging from naturally occuring to synthetic small molecular types.