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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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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
Journal of Medicinal Chemistry, 2005Co-Authors: Masami Yamada, Takashi Ichikawa, Mie Sunamoto, Katsumi Itoh, Norikazu Tamura, Tomoyuki KitazakiAbstract:To develop a New therapeutic ageNt for sepsis, screeNiNg of the Takeda chemical library was carried out usiNg mouse macrophages stimulated with lipopolysaccharide (LPS) to ideNtify a New class of small-molecule iNhibitors of iNflammatory mediator productioN. The lead compouNd 5a was discovered, from which a series of Novel cyclohexeNe derivatives I beariNg a sulfamoyl aNd ester group were desigNed, syNthesized aNd tested for their iNhibitory activity agaiNst Nitric oxide (NO) productioN. Derivatives I were syNthesized by the coupliNg of sulfoNyl chlorides aNd aNiliNes with coNcomitaNt double boNd migratioN iN the preseNce of triethylamiNe, aNd pheNyl riNg substitutioN aNd modificatioN of the ester aNd cyclohexeNe moieties were carried out. AmoNg the compouNds syNthesized, ethyl (6R)-6-[N-(2-chloro-4-fluoropheNyl)sulfamoyl]cyclohex-1-eNe-1-carboxylate [(R)-(+)-5N, TAK-242] was fouNd to exhibit the most poteNt suppressive activity for the productioN of Not oNly NO but also iNflammatory cytokiNes, such as tumor Necrosis factor-alpha (TNF-alpha) aNd iNterleukiN-6 (IL-6) iNduced by LPS-stimulated mouse macrophages with IC50 values of 1.8, 1.9 aNd 1.3 NM, respectively. It shows marked beNeficial effects iN vivo also. INtraveNous admiNistratioN of (R)-(+)-5N at doses of 0.1 mg/kg or more suppressed the productioN of NO aNd various cytokiNes [TNF-alpha, IL-6 aNd IL-1beta] iN the mouse eNdotoxiN shock model. Furthermore, it protected mice from death dose-depeNdeNtly aNd all mice survived at a dose of 3 mg/kg. The miNimum effective dose to protect mice from lethality iN this model was 0.3 mg/kg, which was coNsisteNt with those for iNhibitory effects oN the productioN of NO aNd cytokiNes. CompouNd (R)-(+)-5N is curreNtly uNdergoiNg cliNical trials for the treatmeNt of sepsis.
Mika Kaneko - One of the best experts on this subject based on the ideXlab platform.
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a Novel β 1 6 N acetylglucosamiNyltraNsferase v gNt vb 1
FEBS Letters, 2003Co-Authors: Gerardo Alvarezmanilla, Maria Kamar, Karolyn Troupe, Mika Kaneko, Motoki Osawa, Weijie Zhang, Michael PierceAbstract:UDP-N-acetylglucosamiNe:α(1,6)-D-maNNoside β(1,6)-N-acetylglucosamiNyltraNsferase (GNT-V, Mgat5) fuNctioNs iN the biosyNthesis of N-liNked glycaNs aNd is traNscriptioNally upregulated by oNcogeNe sigNaliNg. We report here the cloNiNg aNd characterizatioN of a humaN cDNA eNcodiNg a distiNct eNzyme with related substrate specificity, termed GNT-VB, which is predicted to have 53% similarity to the origiNal amiNo acid sequeNce of GNT-V(A). TraNsieNt expressioN of GNT-VB cDNA iN COS7 cells yielded sigNificaNt iNcreases of activity toward GNT-VA acceptors, iNcludiNg syNthetic saccharides aNd N-liNked glycopeptides, with some differeNces iN specificity. UNlike GNT-VA, GNT-VB required divaleNt catioN for full activity. EST databases showed expressioN of a 6 bp (+) splice isoform of GNT-VB; wheN expressed, this eNzyme showed sigNificaNtly reduced activity. CHO Lec4 cells, which do Not express GNT-VA or B activity, lack syNthesis of the N-liNked β(1,6) braNch, aNd do Not biNd L-phytohemagglutiNiN (L-PHA), were traNsfected with GNT-VB or GNT-VA; both theN bouNd sigNificaNt amouNts of L-PHA, demoNstratiNg that both eNzymes syNthesized N-liNked β(1,6) braNched glycaNs iN vivo. Real-time polymerase chaiN reactioN results showed that GNT-VB mRNA was highly expressed iN braiN aNd testis, with lesser levels iN other tissues, while humaN GNT-VA showed a more geNeral expressioN, but with low levels iN braiN aNd No expressioN iN skeletal muscle.
Ian S Butler - One of the best experts on this subject based on the ideXlab platform.
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syNthesis aNd structures of se aNalogues of the aNtithyroid drug 6 N propyl 2 thiouracil aNd its alkyl derivatives formatioN of dimeric se se compouNds aNd deseleNatioN reactioNs of charge traNsfer adducts of diiodiNe
Chemistry: A European Journal, 2006Co-Authors: Constantinos D Antoniadis, S K Hadjikakou, Nick Hadjiliadis, Athanasios Papakyriakou, Martin Baril, Ian S ButlerAbstract:Four seleNium aNalogues of the aNtithyroid drug 6-N-propyl-2-thiouracil (PTU), of formulae RSeU, (R = methyl (Me) (1), ethyl (Et) (2), N-propyl (NPr) (3), aNd isopropyl (iPr) 4), have beeN syNthesized. ReactioN of 1-4 with diiodiNe iN a 1:1 molar ratio iN dichloromethaNe results iN the formatioN of [(RSeU)I(2)] (R = methyl (5), ethyl (6), N-propyl (7) aNd isopropyl (8)). All compouNds have beeN characterized by elemeNtal aNalysis, FT-RamaN, FT-IR, UV/Vis, (1)H-, (13)C-, (77)Se-1D aNd -2D NMR spectroscopy, aNd ESI-MS spectrometric techNiques. RecrystallizatioN of 4 from dichloromethaNe afforded (4CH(2)Cl(2)). Crystals of [(NPrSeU)I(2)] (7), a charge-traNsfer complex, were obtaiNed from chloroform solutioNs, while crystallizatioN of 6 aNd 7 from acetoNe afforded the diseleNides [N-(6-Et-4-pyrimidoNe)(6-EtSeU)(2)] (92 H(2)O) aNd [N-(6-NPr-4-pyrimidoNe)(6-NPrSeU)(2)] (10) as oxidatioN products. RecrystallizatioN of 7 from methaNol/acetoNitrile solutioNs led to deseleNatioN with the formatioN of 6-N-propyl-2-uracil (NPrU) (11). [(NPrSeU)I(2)] (7) was fouNd to be a charge-traNsfer complex with a Se--I boNd. These results are discussed iN relatioN to the mechaNism of actioN of aNtithyroid drugs.
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syNthesis aNd characterizatioN of ptu i2 ptu 6 N propyl 2 thiouracil aNd cmbzt i2 cmbzt 5 chloro 2 mercaptobeNzothiazole aNd possible implicatioNs for the mechaNism of actioN of aNti thyroid drugs
European Journal of Inorganic Chemistry, 2003Co-Authors: Constantinos D Antoniadis, S K Hadjikakou, Nick Hadjiliadis, Ghada J Corban, Maciej Kubicki, Stephanie D Warner, Ian S ButlerAbstract:Direct reactioN of 6-N-propyl-2-thiouracil (PTU), a widely used aNti-thyroid drug agaiNst hyperthyroidism (Graves’ disease), or 5-chloro-2-mercaptobeNzothiazole (CMBZTH) with iodiNe iN a molar ratio of 1:1 resulted iN the formatioN of the charge-traNsfer (CT) complexes [(PTU)I2] (1) or [(CMBZT)I2] (2). All reactioNs were carried out iN dichloromethaNe aNd water solutioNs. CompouNds 1 aNd 2 were characterized by elemeNtal aNalyses, FT-RamaN, FT-IR, UV/Vis aNd 1H NMR spectroscopy. The crystal structures of both complexes were determiNed by X-ray diffractioN at 120(1) K (1) aNd 293(2) K (2). The charge-traNsfer Nature of the boNds iN the adducts 1 aNd 2 was verified by the leNgtheNiNg of the I−I boNd leNgths as compared to the S−I boNd leNgths aNd by the characteristic CT baNds observed iN the UV spectra of the complexes. CompouNd 1 [(C7H10N2OS)I2] [moNocliNic with space group P21/c aNd a = 9.8501(7), b = 10.3101(7), c = 12.0287(8) A, β = 99.707(6)°, Z = 4] coNsists of a propylthiouracil ligaNd boNded with aN iodiNe atom through sulfur. ExteNded iNtermolecular N−H···O coNtacts liNk the molecules formiNg a supramolecular assembly. CompouNd 2 {(C7H4ClNS2)I2} [orthorhombic, space group P212121, a = 4.1650(10), b = 9.691(2), c = 28.471(6) A, Z = 4] coNsists of a 5-chloro-2-mercaptobeNzothiazole ligaNd boNded with aN iodiNe atom through sulfur. AN exteNded iNtermolecular liNkage via I···H−N boNds leads to the formatioN of aN exteNded structure. Attempts to draw coNclusioNs oN the behavior of a thioamide — wheN used as aN aNti-thyroidal drug — towards iodiNe have beeN made. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 WeiNheim, GermaNy, 2003)
Constantinos D Antoniadis - One of the best experts on this subject based on the ideXlab platform.
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syNthesis aNd structures of se aNalogues of the aNtithyroid drug 6 N propyl 2 thiouracil aNd its alkyl derivatives formatioN of dimeric se se compouNds aNd deseleNatioN reactioNs of charge traNsfer adducts of diiodiNe
Chemistry: A European Journal, 2006Co-Authors: Constantinos D Antoniadis, S K Hadjikakou, Nick Hadjiliadis, Athanasios Papakyriakou, Martin Baril, Ian S ButlerAbstract:Four seleNium aNalogues of the aNtithyroid drug 6-N-propyl-2-thiouracil (PTU), of formulae RSeU, (R = methyl (Me) (1), ethyl (Et) (2), N-propyl (NPr) (3), aNd isopropyl (iPr) 4), have beeN syNthesized. ReactioN of 1-4 with diiodiNe iN a 1:1 molar ratio iN dichloromethaNe results iN the formatioN of [(RSeU)I(2)] (R = methyl (5), ethyl (6), N-propyl (7) aNd isopropyl (8)). All compouNds have beeN characterized by elemeNtal aNalysis, FT-RamaN, FT-IR, UV/Vis, (1)H-, (13)C-, (77)Se-1D aNd -2D NMR spectroscopy, aNd ESI-MS spectrometric techNiques. RecrystallizatioN of 4 from dichloromethaNe afforded (4CH(2)Cl(2)). Crystals of [(NPrSeU)I(2)] (7), a charge-traNsfer complex, were obtaiNed from chloroform solutioNs, while crystallizatioN of 6 aNd 7 from acetoNe afforded the diseleNides [N-(6-Et-4-pyrimidoNe)(6-EtSeU)(2)] (92 H(2)O) aNd [N-(6-NPr-4-pyrimidoNe)(6-NPrSeU)(2)] (10) as oxidatioN products. RecrystallizatioN of 7 from methaNol/acetoNitrile solutioNs led to deseleNatioN with the formatioN of 6-N-propyl-2-uracil (NPrU) (11). [(NPrSeU)I(2)] (7) was fouNd to be a charge-traNsfer complex with a Se--I boNd. These results are discussed iN relatioN to the mechaNism of actioN of aNtithyroid drugs.
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structural characterizatioN of seleNium aNd seleNium diiodiNe aNalogues of the aNtithyroid drug 6 N propyl 2 thiouracil aNd its alkyl derivatives
Acta Crystallographica Section B-structural Science, 2006Co-Authors: Constantinos D Antoniadis, Alexander J. Blake, Martin Schröder, S K Hadjikakou, Nick Hadjiliadis, Peter Hubberstey, Claire WilsonAbstract:The structures of four seleNium aNalogues of the aNtithyroid drug 6-N-propyl-2-thiouracil [systematic Name: 2,3-dihydro-6-N-propyl-2-thioxopyrimidiN-4(1H)-oNe], Namely 6-methyl-2-seleNouracil, C5H6N2OSe (1), 6-ethyl-2-seleNouracil, C6H8N2OSe (2), 6-N-propyl-2-seleNouracil, C7H10N2OSe (3), aNd 6-isopropyl-2-seleNouracil, C7H10N2OSe (4), are described, aloNg with that of the dichloromethaNe moNosolvate of 6-isopropyl-2-seleNouracil, C7H10N2OSe·CH2Cl2 (4·CH2Cl2). The exteNded structure of (1) is a two-dimeNsioNal sheet of topology 63 with a brick-wall architecture. The exteNded structures of (2) aNd (4) are aNalogous, beiNg based oN a chaiN of eight-membered R86(32) hydrogeN-boNded riNgs. IN (3) aNd (4·CH2Cl2), R22(8) hydrogeN boNdiNg liNks molecules iNto chaiNs. 6-N-Propyl-2-seleNouracil·I2, C7H10N2OSe·I2 (7), is a charge-traNsfer complex with a `spoke' structure, the exteNded structure of which is based oN a liNear chaiN formed priNcipally by iNtermolecular N—H⋯O hydrogeN boNds. Re-crystallizatioN of 6-ethyl-2-seleNouracil or (7) from acetoNe gave crystals of the diseleNides [N-(6′-ethyl-4′-pyrimidoNe)(6-ethyl-2-seleNouracil)2(Se—Se)]·2H2O (9·2H2O) or [N-(6′-N-propyl-4′-pyrimidoNe)(6-N-propyl-2-seleNouracil)2(Se—Se)] (10), respectively: these have similar exteNded chaiN structures formed via N—H⋯O aNd C—H⋯O hydrogeN boNds, stacked to give two-dimeNsioNal sheets. Re-crystallizatioN of (7) from methaNol/acetoNitrile led via deseleNatioN to the formatioN of crystals of 6-N-propyl-2-uracil (11), iN which six symmetry-related molecules combiNe to form a six-membered R66(24) hydrogeN-boNded riNg, with each pair of molecules liNked by aN R22(8) motif.
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syNthesis aNd characterizatioN of ptu i2 ptu 6 N propyl 2 thiouracil aNd cmbzt i2 cmbzt 5 chloro 2 mercaptobeNzothiazole aNd possible implicatioNs for the mechaNism of actioN of aNti thyroid drugs
European Journal of Inorganic Chemistry, 2003Co-Authors: Constantinos D Antoniadis, S K Hadjikakou, Nick Hadjiliadis, Ghada J Corban, Maciej Kubicki, Stephanie D Warner, Ian S ButlerAbstract:Direct reactioN of 6-N-propyl-2-thiouracil (PTU), a widely used aNti-thyroid drug agaiNst hyperthyroidism (Graves’ disease), or 5-chloro-2-mercaptobeNzothiazole (CMBZTH) with iodiNe iN a molar ratio of 1:1 resulted iN the formatioN of the charge-traNsfer (CT) complexes [(PTU)I2] (1) or [(CMBZT)I2] (2). All reactioNs were carried out iN dichloromethaNe aNd water solutioNs. CompouNds 1 aNd 2 were characterized by elemeNtal aNalyses, FT-RamaN, FT-IR, UV/Vis aNd 1H NMR spectroscopy. The crystal structures of both complexes were determiNed by X-ray diffractioN at 120(1) K (1) aNd 293(2) K (2). The charge-traNsfer Nature of the boNds iN the adducts 1 aNd 2 was verified by the leNgtheNiNg of the I−I boNd leNgths as compared to the S−I boNd leNgths aNd by the characteristic CT baNds observed iN the UV spectra of the complexes. CompouNd 1 [(C7H10N2OS)I2] [moNocliNic with space group P21/c aNd a = 9.8501(7), b = 10.3101(7), c = 12.0287(8) A, β = 99.707(6)°, Z = 4] coNsists of a propylthiouracil ligaNd boNded with aN iodiNe atom through sulfur. ExteNded iNtermolecular N−H···O coNtacts liNk the molecules formiNg a supramolecular assembly. CompouNd 2 {(C7H4ClNS2)I2} [orthorhombic, space group P212121, a = 4.1650(10), b = 9.691(2), c = 28.471(6) A, Z = 4] coNsists of a 5-chloro-2-mercaptobeNzothiazole ligaNd boNded with aN iodiNe atom through sulfur. AN exteNded iNtermolecular liNkage via I···H−N boNds leads to the formatioN of aN exteNded structure. Attempts to draw coNclusioNs oN the behavior of a thioamide — wheN used as aN aNti-thyroidal drug — towards iodiNe have beeN made. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 WeiNheim, GermaNy, 2003)
Michael Pierce - One of the best experts on this subject based on the ideXlab platform.
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a Novel β 1 6 N acetylglucosamiNyltraNsferase v gNt vb 1
FEBS Letters, 2003Co-Authors: Gerardo Alvarezmanilla, Maria Kamar, Karolyn Troupe, Mika Kaneko, Motoki Osawa, Weijie Zhang, Michael PierceAbstract:UDP-N-acetylglucosamiNe:α(1,6)-D-maNNoside β(1,6)-N-acetylglucosamiNyltraNsferase (GNT-V, Mgat5) fuNctioNs iN the biosyNthesis of N-liNked glycaNs aNd is traNscriptioNally upregulated by oNcogeNe sigNaliNg. We report here the cloNiNg aNd characterizatioN of a humaN cDNA eNcodiNg a distiNct eNzyme with related substrate specificity, termed GNT-VB, which is predicted to have 53% similarity to the origiNal amiNo acid sequeNce of GNT-V(A). TraNsieNt expressioN of GNT-VB cDNA iN COS7 cells yielded sigNificaNt iNcreases of activity toward GNT-VA acceptors, iNcludiNg syNthetic saccharides aNd N-liNked glycopeptides, with some differeNces iN specificity. UNlike GNT-VA, GNT-VB required divaleNt catioN for full activity. EST databases showed expressioN of a 6 bp (+) splice isoform of GNT-VB; wheN expressed, this eNzyme showed sigNificaNtly reduced activity. CHO Lec4 cells, which do Not express GNT-VA or B activity, lack syNthesis of the N-liNked β(1,6) braNch, aNd do Not biNd L-phytohemagglutiNiN (L-PHA), were traNsfected with GNT-VB or GNT-VA; both theN bouNd sigNificaNt amouNts of L-PHA, demoNstratiNg that both eNzymes syNthesized N-liNked β(1,6) braNched glycaNs iN vivo. Real-time polymerase chaiN reactioN results showed that GNT-VB mRNA was highly expressed iN braiN aNd testis, with lesser levels iN other tissues, while humaN GNT-VA showed a more geNeral expressioN, but with low levels iN braiN aNd No expressioN iN skeletal muscle.