Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.
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.
Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.
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