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BMS-935177

カタログ番号GC31760

BMS-935177 は、ブルトン型チロシンキナーゼ (Btk) の強力かつ選択的な可逆的阻害剤であり、IC50 は 3 nM です。

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BMS-935177 化学構造

Cas No.: 1231889-53-4

サイズ 価格 在庫数 個数
10mM (in 1mL DMSO)
$224.00
在庫あり
2mg
$101.00
在庫あり
5mg
$202.00
在庫あり
10mg
$321.00
在庫あり
25mg
$662.00
在庫あり
50mg
$1,149.00
在庫あり
100mg
$1,930.00
在庫あり

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Kinase experiment:

BMS-935177 is dissolved at 10 mM in DMSO and evaluated at 11 concentrations . To V-bottom 384- well plates are added BMS-935177, human recombinant BTK (1 nM), fluoresceinated peptide (1.5 μM), ATP (20 μM (Km app)), and assay buffer (20 mM HEPES, pH 7.4, 10 mM MgCl2, 0.015% Brij 35 surfactant, and 4 mM DTT in 1.6% DMSO), with a final volume of 30 μL. After incubation at room temperature for 60 min, the reaction is terminated by adding 45 μL of 35 mM EDTA to each sample. The reaction mixture is analyzed on the by electrophoretic separation of the fluorescent substrate and phosphorylated product (excitation, 488 nm; emission, 530 nm)[1].

Animal experiment:

Rats[1]Male Sprague−Dawley rats (255-298 g) are used in the PK studies. To investigate the oral bioavailability of BMS-935177 after crystalline microsuspension doses, rats receive BMS-935177 by oral gavage (1, 5, and 20 mg/kg), T99.5% 10 mM citrate buffer, pH 4, 0.02% DOSS, Methocel A4M. Serial blood samples are obtained after oral dosing at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 h postdose. Plasma samples, obtained by centrifugation at 4 °C (1500-2000g), are stored at −20 °C until analysis[1].Mice[1]Efficacy of BMS-935177 (10 and 30 mg/kg) vs vehicle and dexamethasone (Dex) is studied in a mouse anti-collagen antibody-induced arthritis (CAIA) inflammation model. Mice are injected intraperitoneally (ip) with a mixture of four monoclonal antimouse type II collagen antibodies (1 mg of each). Daily oral dosing is immediately started with vehicle (EtOH:TPGS:PEG300, 5:5:90), BMS-935177 (10 or 30 mg/kg), or dexamethasone (dex, 1 mg/kg). Three days later, the mice are injected ip with 1.25 mg/kg LPS. Thereafter, mice are monitored 3×/ week for the development and severity of paw inflammation[1].

References:

[1]. De Lucca GV, et al. 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]-9H-carbazole-1-carboxamide (BMS-935177). J Med Chem. 2016 Sep 8;59(17):7915-35.

Background

BMS-935177 is a potent and selective reversible inhibitor of Bruton's tyrosine kinase (Btk) with an IC50 of 3 nM.

In B cells stimulated through the BCR, BMS-935177 selectively inhibits several different readouts. BMS-935177 inhibits calcium flux in human Ramos B cells (IC50=27 nM) and inhibits CD69 surface expression in peripheral B cells stimulated with antiIgM and anti-IgG. However, BMS-935177 has no effect on CD69 surface expression in B cells stimulated through the CD40 receptor with CD40 ligand. Against IgG-containing immune complexdriven low affinity activating Fcγ receptor (FcγRIIa and FcγRIII) end points in peripheral blood mononuclear cells (PBMCs), BMS-935177 effectively inhibits TNFα production with an IC50 value of 14 nM. BMS-935177 shows mean IC50 values of 550±100 (n=11) and 2060±240 nM (n=3) in human and mouse whole blood, respectively[1].

When dosed orally once daily at 5, 20, and 45 mg/kg to mice, BMS-935177 inhibits anti-KLH antibodies of the IgG isotype at day 14, with statistically significant reductions at all doses. In satellite mice from this study dosed with 6 at 5 mg/kg, the plasma concentration is maintained above the mouse whole blood BCR-stimulated CD69 IC50 value of 2 μM for only approximately 5 h. At once daily oral doses of 10, 20, and 30 mg/kg beginning on the day of primary immunization, BMS-935177 provides a clear dose-dependent reduction in both the severity and incidence of clinically evident disease in this rodent model of RA. At 10 mg/kg of BMS-935177, disease severity is reduced about 40% compared to vehicle treatment, and the percentage of animals showing any signs of disease is reduced by a third[1].

[1]. De Lucca GV, et al. 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]-9H-carbazole-1-carboxamide (BMS-935177). J Med Chem. 2016 Sep 8;59(17):7915-35.

Chemical Properties

Cas No. 1231889-53-4 SDF
Canonical SMILES O=C(C1=CC=C(C2=CC=CC(N3C=NC4=C(C=CC=C4)C3=O)=C2C)C5=C1NC6=C5C=CC(C(C)(O)C)=C6)N
Formula C31H26N4O3 M.Wt 502.56
溶解度 DMSO : ≥ 130 mg/mL (258.68 mM) Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

Prepare stock solution
1 mg 5 mg 10 mg
1 mM 1.9898 mL 9.9491 mL 19.8981 mL
5 mM 0.398 mL 1.9898 mL 3.9796 mL
10 mM 0.199 mL 0.9949 mL 1.9898 mL
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Average Rating: 5 ★★★★★ (Based on Reviews and 36 reference(s) in Google Scholar.)

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