Login / Signup

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

Andrew K DilgerKumar B PabbisettyJames R CorteIndawati De LuccaTianan FangWu YangDonald J P PintoYufeng WangYeheng ZhuArvind MathurJianqing LiXiaoping HouDaniel SmithDawn SunHuiping ZhangSubramaniam KrishnananthanDauh-Rurng WuJoseph E MyersSteven SheriffKaren A RossiSilvi ChackoJoanna J ZhengMichael A GalellaTheresa ZiembaElizabeth A DierksJeffrey M BozarthYiming WuEarl CrainPancras C WongJoseph M LuettgenRuth R WexlerWilliam R Ewing
Published in: Journal of medicinal chemistry (2021)
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.
Keyphrases