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In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa

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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.

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Acknowledgments

We thank Ms. Cailan Wang for the synthesis of BMS-654457, Mr. Gregory Locke for technical assistance in the enzyme kinetic studies, and Dr. Baomin Xin and Ms. Joanna Zheng for the determination of plasma concentrations of BMS-654457.

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Authors and Affiliations

  1. Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA

    Pancras C. Wong, Carol A. Watson, Earl J. Crain, Mark R. Harpel, Alan R. Rendina, Joseph M. Luettgen, William A. Schumacher & Dietmar A. Seiffert

  2. Cardiovascular Discovery Chemistry, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA

    Mimi L. Quan & Ruth R. Wexler

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  1. Pancras C. Wong
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  2. Mimi L. Quan
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Correspondence to Pancras C. Wong.

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Conflict of interest

Pancras Wong, Mimi Quan, Carol Watson, Earl Crain, Joseph Luettgen, Ruth Wexler, William Schumacher and Dietmar Seiffert are employees of Bristol-Myers Squibb Company. Mark Harpel and Alan Rendina are former employees of Bristol-Myers Squibb Company.

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Wong, P.C., Quan, M.L., Watson, C.A. et al. In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa. J Thromb Thrombolysis 40, 416–423 (2015). https://doi.org/10.1007/s11239-015-1258-7

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  • DOI: https://doi.org/10.1007/s11239-015-1258-7

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