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TAK-242

现货
Catalog No.
A3850
TLR 4信号抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,320.00
现货
5mg
¥ 1,200.00
现货
10mg
¥ 1,800.00
现货
50mg
¥ 7,000.00
现货
100mg
¥ 12,000.00
现货

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Background

IC50: With IC50 of 1.1 to 11 nM, TAK-242 inhibited LPS-induced NO production, tumor necrosis factor-alpha and interleukin (IL)-6 in RAW264.7 cells and mouse peritoneal macrophages [1].

Toll, a member of the Toll-like receptor (TLR) family, was identified as a gene product essential for the development of embryonic dorsoventral polarity in Drosophila melanogaster. Moreover, it has been also found to play a critical role in the antifungal response of flies. TAK-242 (resatorvid), a cyclohexene derivative, is recongnizred as a novel small-molecule compound selectively inhibiting TLR4 signaling.

In vitro: A previous in-vitro study showed that TAK-242 could inhibit the production of lipopolysaccharide-induced inflammatory mediators by binding to the intracellular domain of TLR4 using coimmunoprecipitation approach. Among 10 different human TLRs, TAK-242 selectively bound to TLR4. These findings suggested that TAK-242 could selectively bind to TLR4 and disrupted the interaction of TLR4 with adaptor molecules, thereby inhibiting TLR4 signal transduction and its downstream signaling [2].

In vivo: Preclinical animal study demonostrated that the acute restraint stress exposure upregulateed TLR-4 expression both at the mRNA and protein level in rat. TAK-242 pre-stress administration prevented the accumulation of potentially deleterious inflammatory and oxidative/nitrosative mediators in the brain frontal cortex of rats. These finding s indicated that the use of TAK-242 or other TLR-4 signalling pathway inhibitory compounds could be considered as a potential therapeutic adjuvant strategy to constrain the inflammatory process taking place after stress exposure and in stress-related neuropsychiatric diseases [3].

Clinical trial: To evaluate whether TAK-242, a small-molecule inhibitor of Toll-like receptor-4–mediated signaling, suppresses cytokine levels and improves 28-day all-cause mortality rates in patients with severe sepsis has been conducted in Japan, the U.S. and Europe by Takeda Pharmaceutical Company Limited ("Takeda"). However, following a thorough review of development strategy, Takeda has concluded that TAK-242’s profile does not meet the criteria to support continuation of further development activities. This decision has not been influenced by any concerns over the safety or efficacy of the compound [4].

Reference:
[1] Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, Hazeki O, Kitazaki T, Iizawa Y.  A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex- 1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol. 2006;69(4):1288-95.
[2] Naoko Matsunaga, Noboru Tsuchimori, Tatsumi Matsumoto, and Masayuki Ii.  TAK-242 (Resatorvid), a Small-Molecule Inhibitor of Toll-Like Receptor (TLR) 4 Signaling, Binds Selectively to TLR4 and Interferes with Interactions between TLR4 and Its Adaptor Molecules. Mol Pharmacol 79:34–41, 2011.
[3] Iciar Gárate, Borja García-Bueno, José Luis Mu oz Madrigal, Javier R Caso, Luis Alou, María Luisa Gómez-Lus and Juan Carlos Leza.  Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. Journal of Neuroinflammation 2014, 11:8.
[4] Todd W.  Rice; Arthur P. Wheeler; Gordon R. Bernard; Jean-Louis Vincent; Derek C. Angus; Naoki Aikawa; Ignace Demeyer; Stephen Sainati; Nicholas Amlot; Charlie Cao; Masayuki Ii; Hideyasu Matsuda; Kouji Mouri; Jon Cohen. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med 2010 Vol. 38, No. 8: 1-10.

文献引用

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt361.82
Cas No.243984-11-4
FormulaC15H17ClFNO4S
SynonymsResatorvid;TAK242;TAK 242;CLI-095
Solubility≥18.091 mg/mL in DMSO, ≥100.6 mg/mL in EtOH, <2.45 mg/mL in H2O
Chemical Nameethyl (6R)-6-[(2-chloro-4-fluorophenyl)sulfamoyl]cyclohexene-1-carboxylate
SDFDownload SDF
Canonical SMILESCCOC(=O)C1=CCCCC1S(=O)(=O)NC2=C(C=C(C=C2)F)Cl
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

激酶实验 [1]:

LPS结合PBMC实验

将PBMC悬浮于BSA溶液(含0.1% BSA和0.01%叠氮化钠的磷酸盐缓冲盐水)中。在总体积为50 μL的体系中,将PBMC(3 × 105 个细胞)与TAK-242、抗人CD14单克隆抗体 (MAb) MEM-18,或抗人CC趋化因子受体5 (CCR5) MAb(作为阴性对照)一起置于4 ℃下孵育30分钟。在人血清存在的情况下,将细胞与50 ng/mL LPS(来源于结合了Alexa Fluor488的大肠杆菌血清型O55:B5,其终浓度为1%)置于37 ℃下进一步孵育45分钟。用BSA溶液洗涤2次后,通过CytoACE300细胞荧光计,采用流式细胞术分析1 × 104细胞。对于从4个不同供体所获得的PBMC样本,对每个样本均测定3次。LPS结合百分比为LPS结合细胞百分比之差(在LPS存在的情况下的值减去在LPS不存在的情况下的值)。

细胞实验 [2]:

细胞系

RAW264.7细胞

制备方法

可溶于DMSO。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

1、10、100和1000 nM;15分钟

实验结果

在RAW264.7细胞中,TAK-242抑制LPS诱导的IRAK-1磷酸化。

动物实验 [3]:

动物模型

Wistar Hannover大鼠

给药剂量

0.5 mg/kg;静脉注射

实验结果

在大鼠脑额叶皮层中,TAK-242防止潜在的有害炎症和氧化/亚硝基介质积累。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, Hazeki O, Kitazaki T, Iizawa Y. A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex- 1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol. 2006;69(4):1288-95.

[2]. Naoko Matsunaga, Noboru Tsuchimori, Tatsumi Matsumoto, and Masayuki Ii. TAK-242 (Resatorvid), a Small-Molecule Inhibitor of Toll-Like Receptor (TLR) 4 Signaling, Binds Selectively to TLR4 and Interferes with Interactions between TLR4 and Its Adaptor Molecules. Mol Pharmacol 79:34–41, 2011.

[3] Iciar Gárate, Borja García-Bueno, José Luis Mu?oz Madrigal, Javier R Caso, Luis Alou, María Luisa Gómez-Lus and Juan Carlos Leza. Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. Journal of Neuroinflammation 2014, 11:8.

质量控制

化学结构

TAK-242

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TAK-242

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