Discovery of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2 '- (methylsulfonyl)-[1,1 '-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving a s the point of convergence of the intrinsic and extrinsic pathways. Togethe r with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of pla telets or endothelial cells, factor Xa forms the prothrombinase complex, wh ich is responsible for the proteolysis of prothrombin to catalytically acti ve thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fib rin, thus initiating a process that ultimately leads to clot formation. Rec ently, we reported on a series of isoxazoline and isoxazole monobasic nonco valent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the het erocyclic core, which ultimately led to the discovery of a novel pyrazole S N429 (2b; fXa K-i = 13 pM). We also report on our efforts to improve the or al bioavailability and pharmacokinetic profile of this series while maintai ning subnanomolar potency and in vitro selectivity. This was achieved by re placing the highly basic benzamidine P-1 with a less basic benzylamine moie ty. Further optimization of the pyrazole core substitution and the biphenyl P-4 culminated in the discovery of DPC423 (17h), a highly potent, selectiv e, and orally active factor Xa inhibitor which was chosen for clinical deve lopment.