RATIONAL DESIGN AND SYNTHESIS OF NOVEL, POTENT BIS-PHENYLAMIDINE CARBOXYLATE FACTOR XA INHIBITORS

The molecular modeling studies, rational design, and synthesis of a no vel series of bis-phenylamidine carboxylate compounds which are inhibi tors of factor Xa in the blood coagulation cascade are described. Inhi bition of blood coagulation has been proposed to have several potentia l therapeutic utilities (Kaiser and Hauptmann, Cardiovasc. Drug Rev. 1 994, 12, 225-236). Factor Xa (fXa) holds a central position in the coa gulation cascade (Coleman et al. in Hemostasis and Thrombosis: Basic P rinciples and Clinical Practice, 1994, pp 3-18). Its major role is the generation of thrombin by the proteolytic cleavage of prothrombin. In hibition 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 isol ated 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 pocket s. These modeling studies led to the initial compound (1) which was fo und to have significant inhibitory potency for fXa (K-i = 34 nM). The synthesis of the core structure, structure-activity relationships (SAR ), and proposed binding orientation based on molecular modeling for th is novel bis-phenylamidine series of fXa inhibitors are described.