Document Report Card

ID: ALA1132963

Journal: J Med Chem

Title: Structure-based design of potent, amidine-derived inhibitors of factor Xa: evaluation of selectivity, anticoagulant activity, and antithrombotic activity.

Authors: Wiley MR, Weir LC, Briggs S, Bryan NA, Buben J, Campbell C, Chirgadze NY, Conrad RC, Craft TJ, Ficorilli JV, Franciskovich JB, Froelich LL, Gifford-Moore DS, Goodson T, Herron DK, Klimkowski VJ, Kurz KD, Kyle JA, Masters JJ, Ratz AM, Milot G, Shuman RT, Smith T, Smith GF, Tebbe AL, Tinsley JM.

Abstract: To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitate inhibitor 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-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases. Furthermore, the fXa affinity of compounds in this series (K(ass) = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

CiteXplore: 10715155

DOI: 10.1021/jm9903287