BMS-935177

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效的、选择性的、口服生物可利用的、可逆的 BTK 抑制剂，IC50 为 2.8 nM。

A potent and selective, orally bioavailable, reversible BTK inhibitor with IC50 of 2.8 nM; displays 5-67-fold selectivity over Tec family kinases, 7-fold selectivity over BLK, and 56-fold over Lck in panel of 384 kinases; effectively inhibits TNFα production in PBMCs (IC50=14 nM), inhibits CD69 surface expression in human and mouse whole blood (IC50=0.55 and 2.06 uM, respectively); shows profound efficacy in the CAIA and CIA models of arthritis.

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.

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.

BMS935177

Tyrosine Kinase

BTK

BTK

Inflammation/Immunology

——

1231889-53-4

502.574

C31H26N4O3

>98% (HPLC)

DMSO : ≥ 130 mg/mL 258.68 mM

CC1=C(C=CC=C1N2C=NC3=CC=CC=C3C2=O)C4=C5C6=C(C=C(C=C6)C(C)(C)O)NC5=C(C=C4)C(=O)N

7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide

(-20℃)

With Ice Pack

≥ 2 years