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 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 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 the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound <b>18</b>), a pyridyl biaryl benzimidazole with an excellent <i>in vivo</i> profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation

Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7‑(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]‑9<i>H</i>‑carbazole-1-carboxamide (BMS-935177)

Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydro­quinazolin-3-yl)­phenyl]-9<i>H</i>-carbazole-1-carboxamide <b>6</b> (BMS-935177) was selected to advance into clinical development