Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors

Thrombotic diseases are a major cause of death and morbidity. Factor Xa (Ma) plays a vital role in the regulation of normal homeostasis and abnormal intravascular thrombus development in the blood coagulation cascade. A novel series of Ma inhibitors incorporating an amidino 6,5-fused bicyclic moiety at the P1 position has been designed and synthesized based on molecular modeling studies. Structure-activity relationship (SAR) studies have led to selective subnanomolar Ma inhibitors. The most potent Ma inhibitor in this series (72, SE170) has a potent inhibition constant (K-i = 0.3 nM), is 350-fold selective for Ma over trypsin, and also shows good in vivo efficacy in a rabbit arterio-venous thrombosis model (ID50 = 0.14 mu mol/kg/h). An X-ray crystal structure of 72 complexed to bovine trypsin was completed, and a binding mode of 72 with Ma has been proposed based on modeling with human des-Gla-fXa.