Bruton’s
tyrosine kinase (BTK), a non-receptor tyrosine
kinase, is a member of the Tec family of kinases and is essential
for B cell receptor (BCR) mediated signaling. BTK also plays a critical
role in the downstream signaling pathways for the Fcγ receptor
in monocytes, the Fcε receptor in granulocytes, and the RANK
receptor in osteoclasts. As a result, pharmacological inhibition of
BTK is anticipated to provide an effective strategy for the clinical
treatment of autoimmune diseases such as rheumatoid arthritis and
lupus. This article will outline the evolution of our strategy to
identify a covalent, irreversible inhibitor of BTK that has the intrinsic
potency, selectivity, and pharmacokinetic properties necessary to
provide a rapid rate of inactivation systemically following a very
low dose. With excellent in vivo efficacy and a very desirable tolerability
profile, 5a (branebrutinib, BMS-986195) has advanced
into clinical studies.
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
A search for structurally diversified
Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived
Tyk2 JH2
ligand as a clinical Tyk2 inhibitor currently in late development
for the treatment of psoriasis, began with a survey of six-membered
heteroaryl groups in place of the N-methyl triazolyl
moiety in 6. The X-ray co-crystal structure of an early
lead (12) revealed a potential new binding pocket. Exploration
of the new pocket resulted in two frontrunners for a clinical candidate.
The potential hydrogen bonding interaction with Thr599 in the pocket
was achieved with a tertiary amide moiety, confirmed by the X-ray
co-crystal structure of 29. When the diversity search
was extended to nicotinamides, a single fluorine atom addition was
found to significantly enhance the permeability, which directly led
to the discovery of 7 (BMS-986202) as a clinical Tyk2
inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven
acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will
also be presented.
Fluorine makes the difference: FIBX (see structure), the tetrafluoro derivative of the hypervalent iodine reagent, is more soluble and has higher reactivity than its nonfluorinated counterpart. An efficient synthesis of FIBX and initial reactions are presented. Some of these reactions can be conducted in standard organic solvents. Owing to the increased reactivity, new transformations and catalytic reactions may be possible.
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.
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