Evaluation of a Novel Direct Factor VIIa Inhibitor in Rabbit Models of Arterial Thrombosis and Hemostasis

Abstract number: P0162

Wong P, Crain E, Watson C, Staus A, Luettgen J, Rendina A, Abell L, Knabb R, Baomin X, Zhou J, DeLucca I, Priestley E

BMS-593214 is a synthetic, competitive, and potent inhibitor of human and rabbit coagulation factor VIIa (FVIIa) with K_i of 0.4 and 0.8 nM, respectively. It has greater than 300-fold selectivity over human FIXa, FXa, FXIa, thrombin, trypsin, tPA, urokinase, plasmin and activated protein C, and 15-fold selectivity over plasma kallikrein. The objective of this study was to compare antithrombotic and bleeding time (BT) effects of BMS-593214, and the direct thrombin inhibitor argatroban in anesthetized rabbit models of electrically-induced carotid artery thrombosis and cuticle bleeding, respectively. Compounds were infused IV from 30 to 60 min before artery injury or cuticle bleed until the end of the experiment. Preservation of carotid blood flow (CBF) was used as a marker of antithrombotic effect. Values of antithrombotic EC₅₀ (nM) (plasma concentration that maintained CBF at 50% of control) were 210 for BMS-593214 and 295 for argatroban. Values of cuticle BT (%change over control) determined at the 80% antithrombotic efficacy level were 15 ± 2 for BMS-593214 and 88 ± 12 for argatroban, and -3 ± 2 for the vehicle (n= 5–6 per group), suggesting dissociation of antithrombotic and BT effects for BMS-593214. We evaluated whether BMS-593214 would be effective to inhibit the growth of a preformed thrombus in rabbits. We injured the carotid artery first with electrical stimulation. Fifteen min later, we treated the rabbits with either the vehicle or inhibitor. BMS-593214 and argatroban, but not the vehicle, prevented in a dose-dependent manner the further reduction of CBF (an index of thrombus growth) following electrical stimulation. This study suggests that in an environment of preexisting active thrombosis, BMS-593214 was as effective as argatroban in arresting the growth of arterial thrombus in rabbits. Together, these results suggest that FVIIa inhibition represents a promising antithrombotic target for the development of new therapies for the prevention and treatment of arterial thrombosis.