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

被引：58

作者：

Dilger, Andrew K. ^{[1
]}

Pabbisetty, Kumar B. ^{[1
]}

Corte, James R. ^{[1
]}

De Lucca, Indawati ^{[1
]}

Fang, Tianan ^{[1
]}

Yang, Wu ^{[1
]}

Pinto, Donald J. P. ^{[1
]}

Wang, Yufeng ^{[1
]}

Zhu, Yeheng ^{[1
]}

Mathur, Arvind ^{[1
]}

Li, Jianqing ^{[1
]}

Hou, Xiaoping ^{[1
]}

Smith, Daniel ^{[1
]}

Sun, Dawn ^{[1
]}

Zhang, Huiping ^{[1
]}

Krishnananthan, Subramaniam ^{[1
]}

Wu, Dauh-Rurng ^{[1
]}

Myers, Joseph E., Jr. ^{[1
]}

Sheriff, Steven ^{[1
]}

Rossi, Karen A. ^{[1
]}

Chacko, Silvi ^{[1
]}

Zheng, Joanna J. ^{[1
]}

Galella, Michael A. ^{[1
]}

Ziemba, Theresa ^{[1
]}

Dierks, Elizabeth A. ^{[1
]}

Bozarth, Jeffrey M. ^{[1
]}

Wu, Yiming ^{[1
]}

Crain, Earl ^{[1
]}

Wong, Pancras C. ^{[1
]}

Luettgen, Joseph M. ^{[1
]}

Wexler, Ruth R. ^{[1
]}

Ewing, William R. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 03期

关键词：

COAGULATION-FACTOR XIA; STRUCTURE-BASED DESIGN; SMALL-MOLECULE; THROMBUS PROPAGATION; REDUCED INCIDENCE; BLEEDING-TIME; DEFICIENCY; POTENT; PREVENTION; PYRIDINE;

D O I：

10.1021/acs.jmedchem.1c00613

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1770 / 1785

页数：16

共 45 条

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