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

• Published in: Journal of medicinal chemistry Vol. 65; no. 3; pp. 1770 - 1785
• Main Authors: Dilger, Andrew K, Pabbisetty, Kumar B, Corte, James R, De Lucca, Indawati, Fang, Tianan, Yang, Wu, Pinto, Donald J. P, Wang, Yufeng, Zhu, Yeheng, Mathur, Arvind, Li, Jianqing, Hou, Xiaoping, Smith, Daniel, Sun, Dawn, Zhang, Huiping, Krishnananthan, Subramaniam, Wu, Dauh-Rurng, Myers, Joseph E, Sheriff, Steven, Rossi, Karen A, Chacko, Silvi, Zheng, Joanna J, Galella, Michael A, Ziemba, Theresa, Dierks, Elizabeth A, Bozarth, Jeffrey M, Wu, Yiming, Crain, Earl, Wong, Pancras C, Luettgen, Joseph M, Wexler, Ruth R, Ewing, William R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.02.2022; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Carotid Artery Thrombosis - drug therapy; Chemistry, Medicinal; Factor XIa - antagonists & inhibitors; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - pharmacokinetics; Fibrinolytic Agents - therapeutic use; Life Sciences & Biomedicine; Macaca fascicularis; Mice; Molecular Structure; Pharmacology & Pharmacy; Pyrazoles - administration & dosage; Pyrazoles - chemical synthesis; Pyrazoles - pharmacokinetics; Pyrazoles - therapeutic use; Pyrimidines - administration & dosage; Pyrimidines - chemical synthesis; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Rabbits; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Triazoles - administration & dosage; Triazoles - chemical synthesis; Triazoles - pharmacokinetics; Triazoles - therapeutic use; POTENT; THROMBUS PROPAGATION; REDUCED INCIDENCE; COAGULATION-FACTOR XIA; SMALL-MOLECULE; BLEEDING-TIME; PYRIDINE; PREVENTION; DEFICIENCY; STRUCTURE-BASED DESIGN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00613

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.