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

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.