| Literature DB >> 34494428 |
Andrew K Dilger1, Kumar B Pabbisetty1, James R Corte1, Indawati De Lucca1, Tianan Fang1, Wu Yang1, Donald J P Pinto1, Yufeng Wang1, Yeheng Zhu1, Arvind Mathur1, Jianqing Li1, Xiaoping Hou1, Daniel Smith1, Dawn Sun1, Huiping Zhang1, Subramaniam Krishnananthan1, Dauh-Rurng Wu1, Joseph E Myers1, Steven Sheriff1, Karen A Rossi1, Silvi Chacko1, Joanna J Zheng1, Michael A Galella1, Theresa Ziemba1, Elizabeth A Dierks1, Jeffrey M Bozarth1, Yiming Wu1, Earl Crain1, Pancras C Wong1, Joseph M Luettgen1, Ruth R Wexler1, William R Ewing1.
Abstract
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 Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.Entities:
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Year: 2021 PMID： 34494428 DOI： 10.1021/acs.jmedchem.1c00613
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446