Pinto Donald J P, Orwat Michael J, Smith Leon M, Quan Mimi L, Lam Patrick Y S, Rossi Karen A, Apedo Atsu, Bozarth Jeffrey M, Wu Yiming, Zheng Joanna J, Xin Baomin, Toussaint Nathalie, Stetsko Paul, Gudmundsson Olafur, Maxwell Brad, Crain Earl J, Wong Pancras C, Lou Zhen, Harper Timothy W, Chacko Silvi A, Myers Joseph E, Sheriff Steven, Zhang Huiping, Hou Xiaoping, Mathur Arvind, Seiffert Dietmar A, Wexler Ruth R, Luettgen Joseph M, Ewing William R
Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
J Med Chem. 2017 Dec 14;60(23):9703-9723. doi: 10.1021/acs.jmedchem.7b01171. Epub 2017 Nov 17.
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 K = 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.
因子 XIa（FXIa）是一种参与凝血酶生成放大过程的血液凝固酶。越来越多的证据表明，直接抑制 FXIa 可在维持正常止血功能的同时阻止病理性血栓形成。使用多种降低 FXIa 活性方法的临床前研究，包括 FXIa 的直接抑制剂，已证明具有良好的抗血栓疗效且不会增加出血风险。基于这种潜力，我们致力于寻找强效的 FXIa 抑制剂，重点是发现一种可在医院环境中使用的急性抗血栓药物。在此我们描述了一种强效的 FXIa 临床候选药物 55（FXIa 的解离常数 K = 0.7 nM）的发现，它在血栓形成模型中具有出色的临床前疗效，并且具有适合静脉给药的水溶性。BMS - 962212 是一种可逆、直接且高度选择性的 FXIa 小分子抑制剂。
