BMS-593214, an active site-directed factor VIIa inhibitor: enzyme kinetics, antithrombotic and antihaemostatic studies.
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.
Wong
Pancras C
PC
Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA. pancras.wong@bms.com
Luettgen
Joseph M
JM
Rendina
Alan R
AR
Kettner
Charles A
CA
Xin
Baomin
B
Knabb
Robert M
RM
Wexler
Ruth
R
Priestley
E Scott
ES
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D020134:Catalytic Domain; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015951:Factor Xa / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects*; D006490:Hemostatics / Q000008:administration & dosage / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013925:Thromboplastin / Q000378:metabolism; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control
C553827:BMS 593214; D001565:Benzoates; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D006490:Hemostatics; D006576:Heterocyclic Compounds, 4 or More Rings; D011994:Recombinant Proteins; D013925:Thromboplastin; C103587:recombinant FVIIa; D015942:Factor VIIa; D015951:Factor Xa