The molecular modeling studies, rational design, and synthesis of a novel series of bisphenylamidine carboxylate compounds which are inhibitors of factor Xa in the blood coagulation cascade are described. Inhibition of blood coagulation has been proposed to have several potential therapeutic utilities (Kaiser and Hauptmann, Cardiovasc. Drug Rev. 1994, 12, 225-236). Factor Xa (fXa) holds a central position in the coagulation cascade (Coleman et al. in Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 1994, pp 3-18). Its major role is the generation of thrombin by the proteolytic cleavage of prothrombin. Inhibition of fXa would serve to reduce the formation of platelet clots. The fXa dimer crystal structure (Tulinsky et al., J. Mol. Biol. 1993, 232, 947-966) was used in our molecular modeling studies to design a novel series of fXa inhibitors. We initially docked and minimized isolated small molecule fragments in the S1 and S4 aryl-binding subsites. Subsequently, these fragments were connected with a tether, so as not to disturb the orientation of the fragments in their respective pockets. These modeling studies led to the initial compound (1) which was found to have significant inhibitory potency for fXa (Ki = 34 nM). The synthesis of the core structure, structure-activity relationships (SAR), and proposed binding orientation based on molecular modeling for this novel bis-phenylamidine series of fXa inhibitors are described.

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