Document Report Card

ID: ALA1133520

Journal: J Med Chem

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

Authors: Han Q, Dominguez C, Stouten PF, Park JM, Duffy DE, Galemmo RA, Rossi KA, Alexander RS, Smallwood AM, Wong PC, Wright MM, Luettgen JM, Knabb RM, Wexler RR.

Abstract: Thrombotic diseases are a major cause of death and morbidity. Factor Xa (fXa) plays a vital role in the regulation of normal homeostasis and abnormal intravascular thrombus development in the blood coagulation cascade. A novel series of fXa 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 fXa inhibitors. The most potent fXa inhibitor in this series (72, SE170) has a potent inhibition constant (K(i) = 0.3 nM), is 350-fold selective for fXa over trypsin, and also shows good in vivo efficacy in a rabbit arterio-venous thrombosis model (ID(50) = 0.14 micromol/kg/h). An X-ray crystal structure of 72 complexed to bovine trypsin was completed, and a binding mode of 72 with fXa has been proposed based on modeling with human des-Gla-fXa.

CiteXplore: 11087565

DOI: 10.1021/jm000113t