title: In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa.
abstract: BMS-654457 ((+) 3'-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-2-yl)-4-carbamoyl-5'-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid) is a small-molecule factor XIa (FXIa) inhibitor. We evaluated the in vitro properties of BMS-654457 and its in vivo activities in rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Kinetic studies conducted in vitro with a chromogenic substrate demonstrated that BMS-654457 is a reversible and competitive inhibitor for FXIa. BMS-654457 increased activated partial thromboplastin time (aPTT) without changing prothrombin time. It was equipotent in prolonging the plasma aPTT in human and rabbit, and less potent in rat and dog. It did not alter platelet aggregation to ADP, arachidonic acid and collagen. In vivo, BMS-654457 or vehicle was given IV prior to initiation of thrombosis or cuticle transection. Preservation of integrated carotid blood flow over 90 min (iCBF, % control) was used as a marker of antithrombotic efficacy. BMS-654457 at 0.37 mg/kg + 0.27 mg/kg/h produced almost 90 % preservation of iCBF compared to its vehicle (87 ± 10 and 16 ± 3 %, respectively, n = 6 per group) and increased BT by 1.2 ± 0.04-fold (P < 0.05). At a higher dose (1.1 mg/kg + 0.8 mg/kg/h), BMS-654457 increased BT by 1.33 ± 0.08-fold. This compares favorably to equivalent antithrombotic doses of reference anticoagulants (warfarin and dabigatran) and antiplatelet agents (clopidogrel and prasugrel) which produced four- to six-fold BT increases in the same model. In summary, BMS-654457 was effective in the prevention of arterial thrombosis in rabbits with limited effects on BT. This study supports inhibition of FXIa, with a small-molecule, reversible and direct inhibitor as a promising antithrombotic therapy with a wide therapeutic window.
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA. pancras.wong@bms.com.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Cardiovascular Discovery Chemistry, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Watson
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Earl J
authors.initials: EJ
authors.lastname: Crain
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Harpel
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.affiliation: Cardiovascular Discovery Chemistry, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
mesh_terms: D000818:Animals; D001760:Bleeding Time; D004285:Dogs; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010314:Partial Thromboplastin Time; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*
chemical_list: D005343:Fibrinolytic Agents; D015945:Factor XIa
keywords: Anticoagulant; Blood coagulation; Factor XIa inhibitor; Hemostasis; Thrombosis