Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy

作者：Andrew K. Dilger, Kumar B. Pabbisetty, James R. Corte, Indawati De Lucca, Tianan Fang, Wu Yang, Donald Pinto, Yufeng Wang, Yeheng Zhu, Arvind Mathur, Jianqing Li, Xiaoping Hou, Daniel Smith, Dawn Sun, Huiping Zhang, Subramaniam Krishnananthan, Dauh–Rurng Wu, Joseph E. Myers, S. Sheriff, Karen A. Rossi, Silvi A. Chacko, Joanna J. Zheng, Michael A. Galella, Theresa Ziemba, Elizabeth A. Dierks, Jeffrey M. Bozarth, Yiming Wu, Earl J. Crain, Pancras C. Wong, Joseph M. Luettgen, Ruth R. Wexler, William R. Ewing · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c00613 · 被引用次数：97 · 研究领域：Coagulation, Bradykinin, Polyphosphates, and Angioedema、Vitamin K Research Studies、Mast cells and histamine

Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models ( Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7−12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2′ moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian ( BMS-986177/JNJ-70033093, 17, FXIa K i = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.