DIBASIC (AMIDINOARYL)PROPANOIC ACID-DERIVATIVES AS NOVEL BLOOD-COAGULATION FACTOR XA INHIBITORS

Since activated factor X (FXa) is a coagulant enzyme that generates th rombin and participates in both intrinsic and extrinsic coagulation pa thways, inhibition of FXa may be more effective than inactivation of t hrombin for interrupting blood coagulation. To assess the possible eff ectiveness of FXa inhibition as an anticoagulant, we designed and synt hesized 3-(amidinoaryl)-2-4-(3S)-3-pyrrolidinyloxyl phenylpropanoic acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selectiv e anti-FXa activity in vitro and anticoagulant activity on oral admini stration. The most promising compound, (2S)-2-4-(3S)-1- inyloxyphe nyl-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4, DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 mu M, dou bled plasma recalcification time (PRCT) at 0.5 mu M, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 1 00 mg/kg on oral administration. In contrast with FXa inhibition, 4 sh owed no activity against thrombin (IC50 > 2000 mu M).