7MBO

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

Dilger, A.K., Pabbisetty, K.B., Corte, J.R., De Lucca, I., Fang, T., Yang, W., Pinto, D.J.P., Wang, Y., Zhu, Y., Mathur, A., Li, J., Hou, X., Smith, D., Sun, D., Zhang, H., Krishnananthan, S., Wu, D.R., Myers Jr., J.E., Sheriff, S., Rossi, K.A., Chacko, S., Zheng, J.J., Galella, M.A., Ziemba, T., Dierks, E.A., Bozarth, J.M., Wu, Y., Crain, E., Wong, P.C., Luettgen, J.M., Wexler, R.R., Ewing, W.R.

(2022) J Med Chem 65: 1770-1785

• PubMed: 34494428 Search on PubMed
• DOI: https://doi.org/10.1021/acs.jmedchem.1c00613
• Primary Citation of Related Structures:  
  7MBO


• PubMed 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 K _i = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

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Organizational Affiliation: 

Research and Development, Bristol Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543, United States.