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.

New approaches in tail‐bleeding assay in mice: improving an important method for designing new anti‐thrombotic agents

“…) and BMS‐654,457 (Wong et al . ), which are factor Xa inhibitors, showed prolonged bleeding times using the same technique, corroborating with our results, different from platelet anti‐aggregant drugs that showed different bleeding patterns.…”

Plasma contact factors as therapeutic targets

“…Here we discuss agents that are furthest along in development. BMS-654457 (Bristol-Myers Squibb) is a competitive, reversible, parenterally administered FXIa inhibitor ( K i 0.2 nM) that prolongs the aPTT of human and rabbit plasma, with no effect on the PT or platelet aggregation [151]. It has some activity against plasma kallikrein, which may contribute to aPTT prolongation, and perhaps to efficacy in vivo .…”

“…BMS-654457 prolongs the aPTT in rabbits in a dose-dependent manner, and prevents vessel occlusion in an electrically induced carotid artery thrombosis (ECAT) model. Unlike warfarin or dabigatran, BMS-654457 had no significant effect on bleeding time in the ECAT model [151]. …”

The hemostatic role of factor XI

“…The development of agents to inhibit FXI is fully underway, with the promise of safe and efficacious anti-thrombotic therapies due to the modest role of FXI in hemostasis relative to its role in thrombosis. Specifically, translational approaches are underway to inhibit the enzymatic function of FXI through monoclonal antibodies against FXI which block the activation of FIX or its activation by FXIIa, small-molecule inhibitors that block the active site of FXIa [32] or targets FXIa and allosterically inhibits its activation of FIX [33], or using an antisense oligonucleotide (ASO) to reduce the synthesis of FXI [28,32]. In particular, this antisense approach showed great promise in a clinical trial of patients to reduce the incidence of VTE associated with elective knee operation; the 200 mg and 300 mg ASO regimen was non-inferior and superior, respectively, to enoxaparin (P<0.001), indicating that lowering FXI levels, reduced the risk of VTE associated with knee operation.…”