| Literature DB >> 29077405 |
Donald J P Pinto1, Michael J Orwat1, Leon M Smith1, Mimi L Quan1, Patrick Y S Lam1, Karen A Rossi1, Atsu Apedo1, Jeffrey M Bozarth1, Yiming Wu1, Joanna J Zheng1, Baomin Xin1, Nathalie Toussaint1, Paul Stetsko1, Olafur Gudmundsson1, Brad Maxwell1, Earl J Crain1, Pancras C Wong1, Zhen Lou1, Timothy W Harper1, Silvi A Chacko1, Joseph E Myers1, Steven Sheriff1, Huiping Zhang1, Xiaoping Hou1, Arvind Mathur1, Dietmar A Seiffert1, Ruth R Wexler1, Joseph M Luettgen1, William R Ewing1.
Abstract
Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.Entities:
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Year: 2017 PMID： 29077405 DOI： 10.1021/acs.jmedchem.7b01171
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446