BMS-986142 blocks neoantigen-induced antibody responses.

<p>(<b>A</b>) Primary anti-KLH antibody response over 14 days in mice: day 7 IgM (gray bars) and day 14 IgG (black bars) anti-KLH titers. Data shown are mean ± SEM. (<b>B</b>) Pharmacokinetics of BMS-986142 measured on day 14 of the study with the data represented as time after the morning dose. The dashed line represents the IC50 value determined <i>in vitro</i> against BCR-stimulated CD69 expression on B cells in mouse whole blood. ^*<i>p</i> < 0.05 versus vehicle group, <i>n</i> = 7–10/group.</p

BMS-986142 inhibits RANK-L-induced osteoclastogenesis in human monocytic precursors.

<p>(<b>A</b>) Quantitation of the number of TRAP-positive multinucleated cells per well after 9 days in culture. Data shown are mean ± standard deviation. ^*<i>p</i> < 0.05, ^**<i>p</i> < 0.01 versus vehicle group, n = 3/condition. (<b>B</b>) Representative images.</p

Potencies against functional endpoints in human B cells and peripheral blood mononuclear cells.

<p>Potencies against functional endpoints in human B cells and peripheral blood mononuclear cells.</p

Inhibition of anti-IgM-stimulated phosphorylation of phospholipase C-γ2 in Ramos B cells by BMS-986142.

<p>Inhibition of anti-IgM-stimulated phosphorylation of phospholipase C-γ2 in Ramos B cells by BMS-986142.</p

BMS-986142 co-administered with CTLA-4-Ig shows an enhanced effect against CIA in mice.

<p>(<b>A</b>) Mean clinical scores over the course of the study, (<b>B</b>) mean clinical scores at the end of the study (day 37); BMS-986142 was administered by oral gavage once daily and CTLA-4-Ig by intraperitoneal injection twice weekly, and (<b>C</b>) total inflammation and bone resorption histology scores of the hind paws. Data shown as mean ± SEM. ^*<i>p</i> < 0.05 versus vehicle group, ^**<i>p</i> < 0.01 versus vehicle group, ^#<i>p</i> < 0.05 versus either treatment alone.</p

BMS-986142 is efficacious in the murine CAIA model.

<p>(<b>A</b>) Mean clinical scores, (<b>B</b>) histological evaluation of the right hind paws of CAIA mice, and (<b>C</b>) pharmacokinetics of BMS-986142 on day 12 of the CAIA study. Data shown are mean ± SEM. ^*<i>p</i> < 0.05 versus vehicle group, n = 7–10/group.</p

Therapeutic treatment with BMS-986142 co-administered with etanercept protected from CIA in mice.

<p>(<b>A</b>) Mean clinical scores over the course of the study, (<b>B</b>) mean clinical scores at the end of the study (day 41), (<b>C</b>) pharmacokinetics of BMS-986142 measured on the last day of the study with the data represented as time after the morning dose, (<b>D</b>) bone surface area measurements by micro-CT of the hind limbs, (<b>E</b>) bone mineral density measurements by micro-CT of the hind limbs, and (<b>F</b>) representative images of treatment groups using micro-CT. The dashed line represents the IC50 value determined <i>in vitro</i> against BCR-stimulated CD69 expression on B cells in mouse whole blood. Data for B, D, and E shown as mean ± SEM. ^*<i>p</i> < 0.05 versus vehicle group, ^#<i>p</i> < 0.05 versus either treatment alone, n = 9–10/group.</p

BMS-986142 is efficacious against CIA in mice.

<p>(<b>A</b>) Mean clinical scores over the course of the study, (<b>B</b>) mean clinical scores at the end of the study (day 46), (<b>C</b>) histological evaluation of the right hind paws, (D) plasma cells as measured by FACS analysis performed on spleens from 5 mice per group (3 mice in naïve group; non-immunized mice), (E) CD38 expression (MFI) on splenic CD138+B220low plasma cells, (F) anti-collagen II IgG titers, and (<b>G</b>) pharmacokinetics of BMS-986142 measured on the last day of the study with the data represented as time after the morning dose. The dashed line represents the IC50 value determined <i>in vitro</i> against BCR-stimulated CD69 expression on B cells in mouse whole blood. Data for <b>B</b> through <b>F</b> shown as mean ± SEM. ^*<i>p</i> < 0.05 versus vehicle group, ^#<i>p</i> < 0.05 versus either treatment alone, n = 10/group.</p

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

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, <b>14f</b> (BMS-986142) was advanced into clinical studies