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BMS-593214, an active site-directed factor VIIa inhibitor: Enzyme kinetics, antithrombotic and antihaemostatic studies

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH10-01-0025
Issue: 2010: 104/2 (Aug) pp. 191– 419
Pages: 261-269

BMS-593214, an active site-directed factor VIIa inhibitor: Enzyme kinetics, antithrombotic and antihaemostatic studies

P. C. Wong (1), J. M. Luettgen (1), A. R. Rendina (1), C. A. Kettner (2), B. Xin (3), R. M. Knabb (1), R. Wexler (2), E. S. Priestley (2)

(1) Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA; (2) Discovery Chemistry, Bristol-Myers Squibb Company, Pennington, New Jersey, USA; (3) Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Pennington, New Jersey, USA

Keywords

thrombosis, Animal models, Haemostasis, anticoagulant, tissue factor / factor VIIa

Summary

Factor (F) VIIa in association with tissue factor (TF) is the primary in vivo initiator of blood coagulation and activates FX and FIX to generate thrombin, which plays a key role in the pathogenesis of thrombosis. We evaluated the enzyme kinetics, antithrombotic and antihaemostatic properties of BMS-593214, an active-site, direct FVIIa inhibitor. Studies were conducted in enzymatic assays, and in anesthetised rabbit models of electrically-induced carotid arterial thrombosis (AT), thread-induced vena cava venous thrombosis (VT) and cuticle bleeding time (BT). Antithrombotic efficacy of BMS-593214 given intravenously was evaluated for both the prevention and treatment of AT and VT. BMS-593214 displayed direct, competitive inhibition of human FVIIa in the hydrolysis of a tripeptide substrate with Ki of 5 nM. However, it acted as a noncompetitive inhibitor of the activation of the physiological substrate FX by TF/VIIa with Ki of 9.3 nM. BMS-593214 showed selectivity for FVIIa and exhibited species differences in TF-FVIIa-dependent anticoagulation with similar potency in human and rabbit plasma. BMS-593214 was efficacious in the prevention and treatment models of AT and VT with ED50 values of 1.1 to 3.1 mg/kg. Furthermore, BMS-593214 exhibited a wide therapeutic window with respect to BT. These results suggest that inhibition of FVIIa with small-molecule active-site inhibitors represents a promising antithrombotic approach for the development of new therapies for the prevention and treatment of AT and VT.

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