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.
[reaction: see text] A short and convergent synthesis of 2-aryl-6-chloronicotinamides via regioselective Suzuki coupling of 2,6-dichloronicotinamide with aryl boronic acids is described. Regioselectivity was achieved by chelation of the palladium(0) species to an ester/amide group. The air-stable palladium catalyst PXPd2, when used in reagent-grade methanol with K(2)CO(3) as the base, afforded the best regioselectivity and shortest reaction times among the catalysts screened.
Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
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