| Abstract
| - To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), anamidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitateinhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in fXa affinity and a refined model of the new inhibitors in the fXa active site.Strong support for the computational model was achieved through the acquisition of an X-raycrystal structure using thrombin as a surrogate protein. The amidines in this series show highlevels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases.Furthermore, the fXa affinity of compounds in this series (Kass = 50−500 × 106 L/mol) translateseffectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.
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