Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers

Abstract

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.

Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants

“…Based on PK/PD analysis in SAD and MAD, the derived IC 50 was 0.145 μM. This value was similar with that derived from in vitro evaluation (0.090 μM) [17]. It appears that a 350-mg QD dosing regimen is able to maintain plasma concentrations above the IC50 of CD69 inhibition over the entire dosing interval at steady state.…”

Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care

“…BMS-986142 (6-fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide) was synthesized as described previously [20]. …”

Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers

“…Therapeutic agents that possess chiral axial centers are much less common than chiral compounds with a stereogenic center. Besides lesinurad, other drugs with a chiral axial center on the market are gossypol and telenzepine, as well as a drug under investigation by Bristol-Myers Squibb (BMS) (BMS-986142) (Eveleigh et al, 1989;Watterson et al, 2016;Yang et al, 2018). BMS-986142 is a reversible inhibitor of Bruton's tyrosine kinase, which is being evaluated in clinical trials for the treatment of autoimmune disorders such as lupus and rheumatoid arthritis.…”

“…BMS-986142 is a reversible inhibitor of Bruton's tyrosine kinase, which is being evaluated in clinical trials for the treatment of autoimmune disorders such as lupus and rheumatoid arthritis. The two atropisomeric centers in BMS-986142 are rotationally locked to provide a single, stable atropisomer that produces enhanced potency and selectivity and reduces safety liabilities (Watterson et al, 2016). A significant challenge in the development of a pure atropisomeric drug is the isolation of each atropisomer via chromatographic separation in which one-half of the final material is discarded, unlike a carbon chiral center where the enantiomeric product can be controlled by chemical synthesis (LaPlante et al, 2011a,b).…”