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TAK-242

In stock
Catalog No.
A3850
TLR 4 signaling inhibitor
Grouped product items
SizePriceStock Qty
10mM (in 1mL DMSO)
$132.00
In stock
5mg
$120.00
In stock
10mg
$180.00
In stock
50mg
$700.00
In stock
100mg
$1,200.00
In stock

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Email: [email protected]

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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.

Product Citation

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
Shipping ConditionEvaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request
General tipsFor obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

Protocol

Kinase experiment [1]:

Assay for LPS binding to PBMCs

PBMCs were suspended in BSA solution (phosphate-buffered saline containing 0.1% BSA and 0.01% sodium azide). In a total volume of 50 μL, PBMCs (3 × 105 cells) were incubated with TAK-242, anti-human CD14 monoclonal antibody (MAb) MEM-18, or anti-human CC-chemokine receptor 5 (CCR5) MAb as a negative control for 30 mins at 4 °C. The cells were further incubated with 50 ng/mL LPS from E. coli serotype O55:B5 conjugated with Alexa Fluor 488 per milliliter in the presence of human serum at a final concentration of 1% for 45 mins at 37 °C. After washing twice with BSA solution, 1 × 104 cells were analyzed by flow cytometry using CytoACE300 cytofluorometer. The assays were performed in triplicate for each preparation of PBMCs obtained from four different donors. Specific LPS binding was estimated by subtracting the percentage of LPS-binding cells in the absence of LPS from that in the presence of LPS.

Cell experiment [2]:

Cell lines

RAW264.7 cells

Preparation method

This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reaction Conditions

1, 10, 100 and 1000 nM; 15 mins

Applications

In RAW264.7 cells, TAK-242 inhibited the phosphorylation of IRAK-1 induced by LPS.

Animal experiment [3]:

Animal models

Wistar Hannover rats

Dosage form

0.5 mg/kg; i.v.

Applications

TAK-242 prevented the accumulation of potentially deleterious inflammatory and oxidative/nitrosative mediators in the brain frontal cortex of rats.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

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.

Quality Control

Chemical structure

TAK-242

Related Biological Data

TAK-242

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TAK-242

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TAK-242

Related Biological Data

TAK-242

Related Biological Data

TAK-242

Related Biological Data

TAK-242

Related Biological Data

TAK-242