11 research outputs found
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. <sup>*</sup><i>p</i> < 0.05 versus vehicle group, <i>n</i> = 7–10/group.</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
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. <sup>*</sup><i>p</i> < 0.05, <sup>**</sup><i>p</i> < 0.01 versus vehicle group, n = 3/condition. (<b>B</b>) Representative images.</p
Inhibition of anti-IgM-stimulated phosphorylation of phospholipase C-Îł2 in Ramos B cells by BMS-986142.
<p>Inhibition of anti-IgM-stimulated phosphorylation of phospholipase C-Îł2 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. <sup>*</sup><i>p</i> < 0.05 versus vehicle group, <sup>**</sup><i>p</i> < 0.01 versus vehicle group, <sup>#</sup><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. <sup>*</sup><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. <sup>*</sup><i>p</i> < 0.05 versus vehicle group, <sup>#</sup><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. <sup>*</sup><i>p</i> < 0.05 versus vehicle group, <sup>#</sup><i>p</i> < 0.05 versus either treatment alone, n = 10/group.</p
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-dihydroÂquinazolin-3-yl)Âphenyl]-9<i>H</i>-carbazole-1-carboxamide <b>6</b> (BMS-935177) was
selected to advance into clinical development
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 FcÎł 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