Resatorvid is a novel selective Toll-like receptor 4 signal transduction inhibitor. Resatorvid inhibits various kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-10, macrophage inhibitory protein (MIP)-2 and prostaglandin E2 from lipopolysaccharide (LPS)-stimulated macrophages.
A cell-permeable cyclohexenecarboxylate that disrupts TLR4, but not TLR1-3 or TLR5-10, interaction with adaptor molecules TIRAP and TRAM via direct binding to TLR4 intracellular Cys747 residue.Shown to effectively inhibit TLR4-mediated cellular events (IC
50 = 1.8, 1.3, and 1.9 nM, respectively, against LPS-induced NO, IL-6, and TNF-α production in murine RAW264.7 macrophages)
in vitro and completely prevent LPS- (7 mg/kg, i.p.) induced death in mice (3 mg/kg; i.v.)
in vivo. Also available as a 25 mM solution in DMSO (Cat. No.
508336).
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.
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].
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].
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].
[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.
