title: BMS-593214, an active site-directed factor VIIa inhibitor: enzyme kinetics, antithrombotic and antihaemostatic studies.
abstract: 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.
authors.affiliation: Thrombosis Research, Bristol-Myers Squibb Company, Pennington, New Jersey, USA. pancras.wong@bms.com
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Charles A
authors.initials: CA
authors.lastname: Kettner
authors.forename: Baomin
authors.initials: B
authors.lastname: Xin
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Ruth
authors.initials: R
authors.lastname: Wexler
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
mesh_terms: 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
chemical_list: 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