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

Eur J Pharmacol. 2007 Oct 1;571(2-3):231-9. doi: 10.1016/j.ejphar.2007.06.027. Epub 2007 Jun 29.

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Body Temperature / drug effects
  • Chemokine CXCL2
  • Chemokines / blood
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Interleukins / blood
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred BALB C
  • Multiple Organ Failure / etiology
  • Multiple Organ Failure / prevention & control
  • Nitric Oxide / metabolism
  • Peptidoglycan
  • Shock, Septic / chemically induced
  • Shock, Septic / complications
  • Shock, Septic / drug therapy*
  • Shock, Septic / metabolism
  • Shock, Septic / physiopathology
  • Signal Transduction / drug effects*
  • Staphylococcus aureus
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Time Factors
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / blood

Substances

  • Anti-Inflammatory Agents
  • Chemokine CXCL2
  • Chemokines
  • Cxcl2 protein, mouse
  • Interleukins
  • Lipopolysaccharides
  • Peptidoglycan
  • Sulfonamides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
  • lipopolysaccharide, Escherichia coli O111 B4
  • Nitric Oxide