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.
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.
RORγt
is an important nuclear receptor that regulates the
production of several pro-inflammatory cytokines such as IL-17 and
IL-22. As a result, RORγt has been identified as a potential
target for the treatment of various immunological disorders such as
psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure
and computer-assisted drug design led to the identification of a novel
series of tricyclic RORγt inverse agonists with significantly
improved in vitro activity in the reporter (Gal4) and human whole
blood assays compared to our previous chemotype. Through careful structure
activity relationship, several potent and selective RORγt inverse
agonists have been identified. Pharmacokinetic studies allowed the
identification of the lead molecule 32 with a low peak-to-trough
ratio. This molecule showed excellent activity in an IL-2/IL-23-induced
mouse pharmacodynamic study and demonstrated biologic-like efficacy
in an IL-23-induced preclinical model of psoriasis.
The synthesis, biological evaluation, and structure-activity relationships of a series of 1-naphthols bearing carbon substituents at the 2-position are described. These compounds are potent inhibitors of the 5-lipoxygenase from RBL-1 cells and also inhibit bovine seminal vesicle cyclooxygenase. Structure-activity relationships for these two enzymes are different, implying specific enzyme inhibition rather than a nonspecific antioxidant effect. 2-(Aryl-methyl)-1-naphthols are among the most potent 5-lipoxygenase inhibitors reported (IC50 values generally 0.01-0.2 microM) and show excellent antiinflammatory potency in the mouse arachidonic acid ear edema model. To study the effects of structure on in vitro and in vivo activity, four general features of the molecules were varied: the 2-substituent, the 1-hydroxyl group, substitution on the naphthalene rings, and the 1,2-disubstituted naphthalene unit itself. 2-Benzyl-1-naphthol (5a, DuP 654) shows a very attractive profile of topical antiinflammatory activity and is currently in clinical trials as a topically applied antipsoriatic agent.
A series of 2'-substituted chalcone derivatives has been found to show potent inhibition of the production of IL-1 beta from human peripheral blood monocytes stimulated with lipopolysaccharide (LPS), with IC50 values in the 0.2-5.0-microM range. Some members of the series have also shown inhibition of septic shock induced in mice by injection of LPS, although with low potency. Qualitative structure-activity relationships have shown that the enone is required for activity, which may be mediated by conjugate addition of a biological nucleophile to the chalcone. Electron-poor aromatic rings beta to the ketone give enhanced potency. Although electronic effects in the other ring (directly attached to the ketone) are minimal, this ring must possess an ortho substituent for good activity without cytotoxicity, suggesting a degree of selectivity which would not be expected for simple, nonspecific alkylating agents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.