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GDC-0834

现货
Catalog No.
B3228
有效和选择性BTK抑制剂
组合的产品项目
规格价格库存 数量
50mg
¥ 9,240.00
Ship with 10-15 days
2mg
¥ 2,040.00
Ship with 10-15 days
10mg
¥ 6,000.00
Ship with 10-15 days

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Background

GDC-0834 is a potent and selective Bruton's tyrosine kinase (Btk) inhibitor, The IC50 values in biochemical and cellular assays is 5.9 and 6.4 nM. The in vivo IC50 values in mouse and rat are 1.1 and 5.6 μM, respectively [1]. B cell antigen receptor (BCR) stimulation phosphorylated and activated Btk. Btk gene defects result in a disease named as X-linked agammaglobulinemia which profoundly decreased mature B cells due to a block in B cell development [2].

In vivo: In a rat collagen-induced arthritis (CIA) model, administration of GDC-0834 (30-100 mg/kg) model resulted in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology [1].In PXB chimeric mice with humanized liver, GDC-0834 exhibited low clearance. in most samples from the cohorts dosed orally at 35 and 105 mg GDC-0834, plasma concentrations of GDC-0834 in humans were below the limit of quantitation (<1 ng/ml). High interest in a BTK inhibitor for clinical evaluation and uncertainty in human pharmacokinetic prediction prompted an investigational new drug strategy, in which GDC-0834 was rapidly advanced to a single-dose human clinical trial [3].

References:
[1]. Liu L, Di Paolo J, Barbosa J, et al. Antiarthritis effect of a novel Bruton's tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy[J]. Journal of Pharmacology and Experimental Therapeutics, 2011, 338(1): 154-163.
[2]. Takata M, Kurosaki T. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2[J]. The Journal of experimental medicine, 1996, 184(1): 31-40.
[3]. Liu L, Halladay J S, Shin Y, et al. Significant species difference in amide hydrolysis of GDC-0834, a novel potent and selective Bruton's tyrosine kinase inhibitor[J]. Drug Metabolism and Disposition, 2011, 39(10): 1840-1849.

Chemical Properties

StorageStore at -20°C
M.Wt596.74
Cas No.1133432-50-4
FormulaC33H36N6O3S
SolubilitySoluble in DMSO
Chemical NameN-[3-[6-[4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide
SDFDownload SDF
Canonical SMILESCC1=C(C=CC=C1NC(=O)C2=CC3=C(S2)CCCC3)C4=CN(C(=O)C(=N4)NC5=CC=C(C=C5)C6C(=O)N(CCN6C)C)C
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

酶学实验 [1]:

酶抑制

Lanthascreen方法测定外源肽的磷酸化来量化Btk活性。在25μl的终反应体积中,Btk [人,全长,C末端V5-6×His, Sf9细胞表达,0.075 ng/25μl)与50mM HEPES,pH 7.5,10mM MgCl2,2mM MnCl2,2mM二硫苏糖醇,0.2mM NaVO4,0.01%酪蛋白,0.01%Triton X-100,2.5%甘油和0.4 μM荧光素poly-Glu/Ala/Tyr共孵育。通过加入ATP至25μM(Km的ATP)开始反应。在室温下孵育60分钟后。通过在室温下在60mM EDTA中加入终浓度为2nM Tb-PY20检测抗体30分钟终止反应。在PerkinElmer Envision上,在495和520nm激发光和340nm发射光下测定检测。

细胞实验 [1]:

细胞系

大鼠脾细胞

溶解方法

溶于DMSO。为了获得更高浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

将500μL细胞悬浮液(1×107 cells/ml)与GDC-0834在37℃下孵育1小时,然后用3μg/ml的αIgM(终浓度)刺激3分钟。

应用

在大鼠脾细胞中,GDC-0834抑制pBTK活性,IC50值为6.4±1.6nM。

动物实验 [1]:

动物模型

雌性关节炎Lewis大鼠

剂量

口服GDC-0834,1)空白,1,3,10,30和100 mg/kg,每天两次,间隔12小时;2)空白,10,30和100 mg/kg,每天一次,间隔24小时;3)空白,100 mg/kg,每两天一次,间隔48小时;持续到第16天。

应用

用GDC-0834治疗导致关节炎模型大鼠踝直径-时间曲线下面积显著减少。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. Liu L, Di Paolo J, Barbosa J, Rong H, Reif K, Wong H. Antiarthritis effect of a novel Bruton’s tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy. J Pharmacol Exp Ther. 2011;338(1):154–163.

质量控制

质量控制和MSDS

批次:

化学结构

GDC-0834