10 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-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. <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
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
Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3‑Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders
PI3Kδ plays an important role
controlling immune cell function and has therefore been identified
as a potential target for the treatment of immunological disorders.
This article highlights our work toward the identification of a potent,
selective, and efficacious PI3Kδ inhibitor. Through careful
SAR, the successful replacement of a polar pyrazole group by a simple
chloro or trifluoromethyl group led to improved Caco-2 permeability,
reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity
profile while maintaining potency in the CD69 hWB assay. The optimization
of the aryl substitution then identified a 4′-CN group that
improved the human/rodent correlation in microsomal metabolic stability.
Our lead molecule is very potent in PK/PD assays and highly efficacious
in a mouse collagen-induced arthritis model