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

Pancras C. Wong; Joseph M. Luettgen; Alan R. Rendina; Charles A. Kettner; Baomin Xin; Robert M. Knabb; Ruth R. Wexler; E. Scott Priestley

doi:10.1160/TH10-01-0025

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(02): 261-269
DOI: 10.1160/TH10-01-0025

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Authors

Pancras C. Wong

¹Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA
Joseph M. Luettgen

¹Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA
Alan R. Rendina

¹Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA
Charles A. Kettner

²Discovery Chemistry, Bristol-Myers Squibb Company, Pennington, New Jersey, USA
Baomin Xin

³Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Pennington, New Jersey, USA
Robert M. Knabb

¹Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA
Ruth R. Wexler

²Discovery Chemistry, Bristol-Myers Squibb Company, Pennington, New Jersey, USA
E. Scott Priestley

²Discovery Chemistry, Bristol-Myers Squibb Company, Pennington, New Jersey, USA

Abstract

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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 K_i of 5 nM. However, it acted as a noncompetitive inhibitor of the activation of the physiological substrate FX by TF/VIIa with K_i 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.

Keywords

Anticoagulant - animal models - haemostasis - thrombosis - tissue factor / factor VIIa

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References

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