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Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model.

Abstract：

:Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule that selectively inhibits Toll-like receptor 4-mediated signaling, inhibits various kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-10, macrophage inhibitory protein (MIP)-2 and prostaglandin E2 from lipopolysaccharide (LPS)-stimulated macrophages. The effects of TAK-242 were evaluated in a mouse model of endotoxin shock. Intravenous administration of TAK-242 to mice 1 h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-alpha, IL-1beta, IL-6, IL-10, MIP-2, and NO metabolites. TAK-242 protected mice from LPS-induced lethality in a similar dose-dependent manner, and rescued 100% of mice at a dose of 1 mg/kg. Interestingly, TAK-242 worked quickly, and showed beneficial effects even when administered after LPS challenge. Even though increases in serum levels of IL-6 and hypothermia were already evident 2 h after LPS challenge, TAK-242 administration inhibited further increase in IL-6 levels and decrease in body temperature. LPS-induced increases in serum levels of organ dysfunction markers, such as alanine aminotransferase, total bilirubin, and blood urea nitrogen, were also significantly suppressed by post-treatment as well as pre-treatment. Furthermore, administration of 3 mg/kg TAK-242 significantly increased survival of mice, even when given 4 h after LPS challenge. These results suggest that TAK-242 protects mice against LPS-induced lethality by inhibiting production of multiple cytokines and NO. TAK-242 has a quick onset of action and provides significant benefits by post-treatment, suggesting that it may be a promising drug candidate for the treatment of sepsis.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Sha T,Sunamoto M,Kitazaki T,Sato J,Ii M,Iizawa Y

doi

10.1016/j.ejphar.2007.06.027

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

231-9

issue

2-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(07)00734-0

journal_volume

571

pub_type

杂志文章

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Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model.