BISBENZAMIDINE ISOXAZOLINE DERIVATIVES AS FACTOR XA INHIBITORS

Factor Xa is an important serine protease in the blood coagulation cas cade. It generates thrombin and holds the central position that links the intrinsic and extrinsic activation mechanism in the final common p athway of coagulation. Therefore, inhibition of factor Xa has potentia l therapeutic applications in the treatment of both arterial and venou s thrombosis. We have designed and synthesized a series of bisbenzamid ine isoxazoline derivatives as factor Xa inhibitors. The most potent c ompound in this series has a K-i of 18 nM against factor Xa. (C) 1997 The DuPont Merck Pharmaceutical Company. Published by Elsevier Science Ltd.