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Featured researches published by nan Masayuki.


Molecular Pharmacology | 2011

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.

Naoko Matsunaga; Noboru Tsuchimori; Tatsumi Matsumoto; Masayuki

TAK-242 (resatorvid), a small-molecule–specific inhibitor of Toll-like receptor (TLR) 4 signaling, inhibits the production of lipopolysaccharide-induced inflammatory mediators by binding to the intracellular domain of TLR4. Cys747 in TLR4 has been identified previously as the binding site of TAK-242. However, the mechanism by which TAK-242 inhibits TLR4 signaling after binding to TLR4 remains unknown. The present study demonstrated, using coimmunoprecipitation, that TAK-242 interferes with protein-protein interactions between TLR4 and its adaptor molecules. Among 10 different human TLRs, TAK-242 selectively bound to TLR4. The time course of the inhibitory effect of TAK-242 on inflammatory mediator production corresponded to that of the binding of TAK-242 to TLR4. TAK-242 inhibited the association of TLR4 with Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) or Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-β-related adaptor molecule (TRAM) in human embryonic kidney (HEK) 293 cells overexpressing TLR4, MD-2, and TIRAP or TRAM, respectively. TAK-242 inhibited the TIRAP-mediated activation of nuclear factor κB (NF-κB) and the TRAM-mediated activation of NF-κB and interferon-sensitive response element in HEK293 cells stably expressing TLR4, MD-2, and CD14. The activation of endogenous interleukin-1 receptor-associated kinase in RAW264.7 cells was also inhibited by TAK-242 treatment. These findings suggest that TAK-242 binds selectively to TLR4 and subsequently disrupts the interaction of TLR4 with adaptor molecules, thereby inhibiting TLR4 signal transduction and its downstream signaling events. This work proposes a novel paradigm of a small molecule capable of disrupting protein-protein interactions.


Brain Research | 1996

β-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity

Masayuki; Mie Sunamoto; Koji Ohnishi; Yuzo Ichimori

beta-Amyloid protein (A beta) is the major component of the senile plaques in Alzheimers disease (AD), and microglial cells have been shown to be closely associated with these plaques. However, the roles of A beta and microglial cells in pathogenesis of AD remain unclear. Incubation of rat microglial cells with A beta(1-40) caused a significant increase in nitrite, a stable metabolite of nitric oxide (NO), in culture media, while there was no detectable increase in nitrite in astrocyte-rich glial cells or cortical neurons after incubation with A beta(1-40). Nitrite production by microglial cells was also induced by A beta(1-42), but not A beta(25-35). An inhibitor of NO synthase, NG-monomethyl-L-arginine (NMMA), as well as dexamethasone and actinomycin D, dose-dependently inhibited this nitrite production. Among the various cytokines investigated such as interleukin-1, interleukin-6, tumor necrosis factor-alpha and interferon-gamma (IFN-gamma), only IFN-gamma markedly enhanced A beta-dependent nitrite production. Cultured cortical neurons were injured by microglial cells stimulated with A beta in a dose-dependent manner in the presence of IFN-gamma. Neurotoxicity caused by the A beta plus IFN-gamma-stimulated microglial cells was significantly attenuated by NMMA. Thus, although further investigations into the effect of A beta on human microglial cells are needed, it is likely that A beta-induced NO production by microglial cells is one mechanism of the neuronal death in AD.


European Journal of Pharmacology | 2008

TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain

Tomohiro Kawamoto; Masayuki; Tomoyuki Kitazaki; Yuji Iizawa; Hiroyuki Kimura

TAK-242, a small-molecule antisepsis agent, has shown to suppress lipopolysaccharide (LPS)-induced inflammation. In this study, we demonstrate that TAK-242 is a selective inhibitor of Toll-like receptor (TLR)-4 signaling. TAK-242 almost completely suppressed production of nitric oxide (NO) or tumor necrosis factor (TNF)-alpha induced by a TLR4-specific ligand, ultra-pure LPS, in mouse RAW264.7, human U-937 and P31/FUJ cells, whereas this agent showed little effect on other TLR ligands, Pam(3)CSK(4) (TLR1/2), peptidoglycan (TLR2/6), double strand RNA (TLR3), R-848 (TLR7) and CpG oligonucleotide (TLR9). Furthermore, TAK-242 potently inhibited nuclear factor (NF)-kappaB activation induced by ultra-pure LPS in HEK293 cells transiently expressing TLR4 and co-receptors, myeloid differentiation protein-2 (MD2) and CD14, whereas this agent showed little effect on other TLRs, TLR1/2, TLR2/6, TLR3, TLR5, TLR7 and TLR9. TAK-242 also inhibited ligand-independent NF-kappaB activation resulting from over-expression of TLR4. Although chimera receptors, which are consist of the extracellular domain of CD4 and the intracellular domain of human or mouse TLR4, showed constitutive NF-kappaB activation, TAK-242 potently inhibited the signaling from CD4-TLR4 chimera receptors. In contrast, the NF-kappaB activation mediated by TLR4 adaptors, myeloid differentiation factor 88 (MyD88), TIR-associated protein (TIRAP), Toll/IL-1R homology (TIR)-domain-containing adaptor protein-inducing interferon-beta (TRIF) or TRIF-related adaptor molecule (TRAM) was not affected by TAK-242. TAK-242 is therefore a selective inhibitor of signaling from the intracellular domain of TLR4 and represents a novel therapeutic approach to the treatment of TLR4-mediated diseases.


Bioorganic & Medicinal Chemistry | 2008

Novel cyclohexene derivatives as anti-sepsis agents : Synthetic studies and inhibition of NO and cytokine production

Masami Yamada; Takashi Ichikawa; Masayuki; Katsumi Itoh; Norikazu Tamura; Tomoyuki Kitazaki

In order to develop an anti-sepsis agent, a series of cyclohexene derivatives were synthesized and evaluated for their biological activities. Through modification of the sulfonamide spacer moiety depicted by formula II, it was found that the benzylsulfone derivative 10a had potent inhibitory activity against the production of NO. Further modifications of the phenyl ring, ester moiety, and benzyl position of benzylsulfone derivatives III were carried out. Among these compounds, (R)-(+)-10a and (6R, 1S)-(+)-22a showed strong inhibitory activity not only against NO production but also against inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in vitro. Furthermore, (R)-(+)-10a and (6R, 1S)-(+)-22a protected mice from LPS-induced lethality in a dose-dependent manner.


Molecular Pharmacology | 2006

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.

Masayuki; Naoko Matsunaga; Kaoru Hazeki; Kazuyo Nakamura; Katsunori Takashima; Tsukasa Seya; Osamu Hazeki; Tomoyuki Kitazaki; Yuji Iizawa


European Journal of Pharmacology | 2007

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

Takukyu Sha; Mie Sunamoto; Tomoyuki Kitazaki; Jun Sato; Masayuki; Yuji Iizawa


Journal of Medicinal Chemistry | 2005

Discovery of Novel and Potent Small-Molecule Inhibitors of NO and Cytokine Production as Antisepsis Agents: Synthesis and Biological Activity of Alkyl 6-(N-Substituted sulfamoyl)cyclohex-1-ene-1-carboxylate

Masami Yamada; Takashi Ichikawa; Masayuki; Mie Sunamoto; Katsumi Itoh; Norikazu Tamura; Tomoyuki Kitazaki


Archive | 1999

Cycloalkene derivatives, process for producing the same, and use

Yuzo Ichimori; Masayuki; Katsumi Itoh; Tomoyuki Kitazaki; Junji Yamada


Archive | 2003

Severe sepsis preventive therapeutic agent

Masayuki; Yuji Iizawa; Tomoyuki Kitazaki; Kazuki Kubo


Archive | 2000

Substituted aromatic-ring compounds, process for producing the same and use

Norikazu Tamura; Takashi Ichikawa; Masayuki

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Tomoyuki Kitazaki

Takeda Pharmaceutical Company

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Yuji Iizawa

Takeda Pharmaceutical Company

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Junji Yamada

Takeda Pharmaceutical Company

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Katsumi Itoh

Takeda Pharmaceutical Company

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Yuzo Ichimori

Takeda Pharmaceutical Company

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Mie Sunamoto

Takeda Pharmaceutical Company

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Naoko Matsunaga

Takeda Pharmaceutical Company

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Katsunori Takashima

Takeda Pharmaceutical Company

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Norikazu Tamura

Takeda Pharmaceutical Company

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Takashi Ichikawa

Takeda Pharmaceutical Company

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