Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa K = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.
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 (WeitzJ. I.ChanN. C.
Weitz, J. I.
Chan, N. C.
Arterioscler. Thromb.
Vasc. Biol.201939712).
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.
A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa K = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.
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A multi-block compositing graft concept is investigated to fabricate proton exchange membranes. The prepared membranes demonstrate excellent ion conductive capacity and better fuel cell performance over the entire relative humidity conditions, compared to Nafion.
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