The Experts below are selected from a list of 60 Experts worldwide ranked by ideXlab platform
Yuji Iizawa - One of the best experts on this subject based on the ideXlab platform.
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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
Molecular Pharmacology, 2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were similar in human PBMCs, monocytes, and macrophages. TAK-242 inhibited mRNA expression of IL-6 and TNF-α induced by LPS and interferon-γ in RAW264.7 cells. The phosphorylation of mitogen-activated protein kinases induced by LPS was also inhibited in a concentration-dependent manner. However, TAK-242 did not antagonize the binding of LPS to the cells. It is noteworthy that TAK-242 suppressed the cytokine production induced by Toll-like receptor (TLR) 4 ligands, but not by ligands for TLR2, -3, and -9. In addition, IL-1β-induced IL-8 production from human PBMCs was not markedly affected by TAK-242. These data suggest that TAK-242 suppresses the production of multiple cytokines by selectively inhibiting TLR4 intracellular signaling. Finally, TAK-242 is a novel small molecule TLR4 signaling inhibitor and could be a promising therapeutic agent for inflammatory diseases, whose pathogenesis involves TLR4.
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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
2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor- (TNF-), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPSstimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were
Tomoyuki Kitazaki - One of the best experts on this subject based on the ideXlab platform.
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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
Molecular Pharmacology, 2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were similar in human PBMCs, monocytes, and macrophages. TAK-242 inhibited mRNA expression of IL-6 and TNF-α induced by LPS and interferon-γ in RAW264.7 cells. The phosphorylation of mitogen-activated protein kinases induced by LPS was also inhibited in a concentration-dependent manner. However, TAK-242 did not antagonize the binding of LPS to the cells. It is noteworthy that TAK-242 suppressed the cytokine production induced by Toll-like receptor (TLR) 4 ligands, but not by ligands for TLR2, -3, and -9. In addition, IL-1β-induced IL-8 production from human PBMCs was not markedly affected by TAK-242. These data suggest that TAK-242 suppresses the production of multiple cytokines by selectively inhibiting TLR4 intracellular signaling. Finally, TAK-242 is a novel small molecule TLR4 signaling inhibitor and could be a promising therapeutic agent for inflammatory diseases, whose pathogenesis involves TLR4.
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optically active Cyclohexene Derivative as a new antisepsis agent an efficient synthesis of ethyl 6r 6 n 2 chloro 4 fluorophenyl sulfamoyl cyclohex 1 ene 1 carboxylate tak 242
Chemical & Pharmaceutical Bulletin, 2006Co-Authors: Masami Yamada, Takashi Ichikawa, Toru Yamano, Fumio Kikumoto, Yuji Nishikimi, Norikazu Tamura, Tomoyuki KitazakiAbstract:Two new synthetic methods were established for the efficient synthesis of optically active Cyclohexene antisepsis agent, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-1: TAK-242)]. The first method involved recrystallization from methanol of the diastereomeric mixture (6RS,1'R)-7, obtained by esterification of carboxylic acid 3 with (S)-1-(4-nitrophenyl)ethanol [(S)-5)] to give the desired isomer (6R,1'R)-7 with 99% de in 32% yield. Subsequent catalytic hydrogenolysis and esterification gave (R)-1 with >99% ee. The second method employed enantioselective hydrolysis of acetoxymethyl ester 9a (prepared by alkylation of 3 with bromomethyl acetate) with Lipase PS-D to give the eutomeric enantiomer (R)-9a with excellent enantioselectivity (>99% ee) and high yield (48%). The desired (R)-1 was then obtained by transesterification with ethanol in the presence of concentrated sulfuric acid without loss of ee. Of these, the procedure employing enzymatic kinetic resolution using Lipase PS-D is the more efficient and practical preparation of (R)-1.
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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
2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor- (TNF-), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPSstimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were
Naoko Matsunaga - One of the best experts on this subject based on the ideXlab platform.
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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
Molecular Pharmacology, 2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were similar in human PBMCs, monocytes, and macrophages. TAK-242 inhibited mRNA expression of IL-6 and TNF-α induced by LPS and interferon-γ in RAW264.7 cells. The phosphorylation of mitogen-activated protein kinases induced by LPS was also inhibited in a concentration-dependent manner. However, TAK-242 did not antagonize the binding of LPS to the cells. It is noteworthy that TAK-242 suppressed the cytokine production induced by Toll-like receptor (TLR) 4 ligands, but not by ligands for TLR2, -3, and -9. In addition, IL-1β-induced IL-8 production from human PBMCs was not markedly affected by TAK-242. These data suggest that TAK-242 suppresses the production of multiple cytokines by selectively inhibiting TLR4 intracellular signaling. Finally, TAK-242 is a novel small molecule TLR4 signaling inhibitor and could be a promising therapeutic agent for inflammatory diseases, whose pathogenesis involves TLR4.
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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
2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor- (TNF-), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPSstimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were
Osamu Hazeki - One of the best experts on this subject based on the ideXlab platform.
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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
Molecular Pharmacology, 2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were similar in human PBMCs, monocytes, and macrophages. TAK-242 inhibited mRNA expression of IL-6 and TNF-α induced by LPS and interferon-γ in RAW264.7 cells. The phosphorylation of mitogen-activated protein kinases induced by LPS was also inhibited in a concentration-dependent manner. However, TAK-242 did not antagonize the binding of LPS to the cells. It is noteworthy that TAK-242 suppressed the cytokine production induced by Toll-like receptor (TLR) 4 ligands, but not by ligands for TLR2, -3, and -9. In addition, IL-1β-induced IL-8 production from human PBMCs was not markedly affected by TAK-242. These data suggest that TAK-242 suppresses the production of multiple cytokines by selectively inhibiting TLR4 intracellular signaling. Finally, TAK-242 is a novel small molecule TLR4 signaling inhibitor and could be a promising therapeutic agent for inflammatory diseases, whose pathogenesis involves TLR4.
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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
2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor- (TNF-), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPSstimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were
Tsukasa Seya - One of the best experts on this subject based on the ideXlab platform.
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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
Molecular Pharmacology, 2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were similar in human PBMCs, monocytes, and macrophages. TAK-242 inhibited mRNA expression of IL-6 and TNF-α induced by LPS and interferon-γ in RAW264.7 cells. The phosphorylation of mitogen-activated protein kinases induced by LPS was also inhibited in a concentration-dependent manner. However, TAK-242 did not antagonize the binding of LPS to the cells. It is noteworthy that TAK-242 suppressed the cytokine production induced by Toll-like receptor (TLR) 4 ligands, but not by ligands for TLR2, -3, and -9. In addition, IL-1β-induced IL-8 production from human PBMCs was not markedly affected by TAK-242. These data suggest that TAK-242 suppresses the production of multiple cytokines by selectively inhibiting TLR4 intracellular signaling. Finally, TAK-242 is a novel small molecule TLR4 signaling inhibitor and could be a promising therapeutic agent for inflammatory diseases, whose pathogenesis involves TLR4.
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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
2006Co-Authors: Naoko Matsunaga, Tomoyuki Kitazaki, Kaoru Hazeki, Kazuyo Nakamura, Katsunori Takashima, Tsukasa Seya, Osamu Hazeki, Yuji IizawaAbstract:Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor- (TNF-), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPSstimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were
