Chem. Pharm. Bull. 55(10) 1494—1504 (2007)

tention as a promising drug candidate for anticoagulation. FXa, a serine protease in the blood coagulation cascade, is essential for the formation of thrombin. It plays an important role in the coagulation cascade at the convergent point of the intrinsic and the extrinsic pathway. FXa inhibitor is expected to be a novel antithrombotic with potential for the treatment and prevention of thromboembolic diseases. In previous papers, we reported the syntheses and FXa inhibitory activities of bisamidine compounds having indoline moiety in the center of the molecule. In these studies, we found that (R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7amidinonaphthalen-2-yl)-1-(ethanesulfonyl)indoline ((R)-1) and ({(R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)indolin-1-yl}sulfonyl)acetic acid ((R)-2) exhibited potent FXa inhibitory activities (Fig. 1). However, these compounds also exhibited potent inhibitory activities against trypsin which belongs to a serine protease family. In general, compounds having selective inhibitory activity against target enzyme were favorable as drug candidates because of less possibility of unexpected adverse reaction. From this viewpoint, we searched for a potent and selective FXa inhibitor. Herein, we describe the synthesis and structure–activity relationships (SARs) and FXa selectivity of these compounds.