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Antiarthritic Drug

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Tatsuo Tsuri – One of the best experts on this subject based on the ideXlab platform.

  • Short synthesis of tert-butyl-hydroxylated 3,5-di-tert-butyl-4-hydroxybenzaldehyde: Synthesis of tert-butyl-hydroxylated S-2474.
    Journal of Organic Chemistry, 2003
    Co-Authors: Masanao Inagaki, Saichi Matsumoto, Tatsuo Tsuri

    Abstract:

    We have developed a very short synthesis of tert-butyl-hydroxylated di-tert-butyl-4-hydroxybenzaldehyde in which the HBr-DMSO system is used as an effective oxidant (overall yield of 45% for the entire four-step process from 2-tert-butyl-p-cresol). We also accomplished the synthesis of a major metabolite of the Antiarthritic Drug candidate S-2474.

  • highly e selective and effective synthesis of Antiarthritic Drug candidate s 2474 using quinone methide derivatives
    Journal of Organic Chemistry, 2002
    Co-Authors: Masanao Inagaki, Nobuhiro Haga, Makoto Kobayashi, Naoki Ohta, Susumu Kamata, Tatsuo Tsuri

    Abstract:

    We have developed an efficient and E-selective synthesis of an Antiarthritic Drug candidate (E)−(5)−(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474; 1), in which α-methoxy-p-quinone methide is used as a key intermediate. α-Methoxy-p-quinone methide was revealed to be an equivalent to a p-hydroxy protected benzaldehyde. It reacts smoothly with α-sulfonyl carbanion to give 1,6-addition intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.

  • Novel Antiarthritic Agents with 1,2-Isothiazolidine-1,1-dioxide (γ-Sultam) Skeleton: Cytokine Suppressive Dual Inhibitors of Cyclooxygenase-2 and 5-Lipoxygenase
    Journal of Medicinal Chemistry, 2000
    Co-Authors: Masanao Inagaki, Tatsuo Tsuri, Hirokuni Jyoyama, Katsutoshi Yamada, Mika Kobayashi, Yozo Hori, Akinori Arimura, Kiyoshi Yasui, Kouji Ohno

    Abstract:

    Various 1,2-isothiazolidine-1,1-dioxide (γ-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the γ-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474) was selected as an Antiarthritic Drug candidate and is now under clinical trials. The structure−activity relationships (SAR) examined and some pharmacological evaluations are described.

Inchan Youn – One of the best experts on this subject based on the ideXlab platform.

  • prediction of Antiarthritic Drug efficacies by monitoring active matrix metalloproteinase 3 mmp 3 levels in collagen induced arthritic mice using the mmp 3 probe
    Molecular Pharmaceutics, 2014
    Co-Authors: Kyeongsoon Park, Sung Jae Choi, Kuiwon Choi, Ick Chan Kwon, Soo Young Yoon, Inchan Youn

    Abstract:

    Active matrix metalloproteinase-3 (MMP-3) is a prognostic marker of rheumatoid arthritis (RA). We recently developed an MMP-3 probe that can specifically detect the active form of MMP-3. The aim of this study was to investigate whether detection and monitoring of active MMP-3 could be useful to predict therapeutic Drug responses in a collagen-induced arthritis (CIA) model. During the period of treatment with Drugs such as methotrexate (MTX) or infliximab (IFX), MMP-3 mRNA and protein levels were correlated with fluorescence signals in arthritic joint tissues and in the serum of CIA mice. Also, bone volume density and erosion in the knee joints and the paws of CIA mice were measured with microcomputed tomography (micro-CT), X-ray, and histology to confirm Drug responses. In joint tissues and serum of CIA mice, strong fluorescence signals induced by the action of active MMP-3 were significantly decreased when Drugs were applied. The decrease in RA scores in Drug-treated CIA mice led to fluorescence reductio…

Masanao Inagaki – One of the best experts on this subject based on the ideXlab platform.

  • studies on the new Antiarthritic Drug candidate s 2474
    Yakugaku Zasshi-journal of The Pharmaceutical Society of Japan, 2003
    Co-Authors: Masanao Inagaki

    Abstract:

    : Various 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butyl-phenol substituent, were prepared. Some compounds that have a lower alkyl group at the 2-position of the gamma-sultam skeleton showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin-1 (IL-1) in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidence)-2-ethyl-1,2- isothiazolidine-1,1-dioxide (S-2474) was selected as an Antiarthritic Drug candidate. The structure-activity relationships examined and some pharmacological evaluations are described. Furthermore, we have developed an efficient and E-selective synthesis of S-2474, in which alpha-methoxy-p-quinone methide is used as a key intermediate. alpha-Methoxy-p-quinone methide was revealed to be equivalent to a p-hydroxy-protected benzaldehyde. It reacts smoothly with alpha-sulfonyl carbanion to give 1,6-addition intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.

  • Short synthesis of tert-butyl-hydroxylated 3,5-di-tert-butyl-4-hydroxybenzaldehyde: Synthesis of tert-butyl-hydroxylated S-2474.
    Journal of Organic Chemistry, 2003
    Co-Authors: Masanao Inagaki, Saichi Matsumoto, Tatsuo Tsuri

    Abstract:

    We have developed a very short synthesis of tert-butyl-hydroxylated di-tert-butyl-4-hydroxybenzaldehyde in which the HBr-DMSO system is used as an effective oxidant (overall yield of 45% for the entire four-step process from 2-tert-butyl-p-cresol). We also accomplished the synthesis of a major metabolite of the Antiarthritic Drug candidate S-2474.

  • highly e selective and effective synthesis of Antiarthritic Drug candidate s 2474 using quinone methide derivatives
    Journal of Organic Chemistry, 2002
    Co-Authors: Masanao Inagaki, Nobuhiro Haga, Makoto Kobayashi, Naoki Ohta, Susumu Kamata, Tatsuo Tsuri

    Abstract:

    We have developed an efficient and E-selective synthesis of an Antiarthritic Drug candidate (E)−(5)−(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (S-2474; 1), in which α-methoxy-p-quinone methide is used as a key intermediate. α-Methoxy-p-quinone methide was revealed to be an equivalent to a p-hydroxy protected benzaldehyde. It reacts smoothly with α-sulfonyl carbanion to give 1,6-addition intermediates, which can be further processed to provide S-2474 directly in the presence of a base. This procedure gives S-2474 as an almost single isomer on the benzylidene double bond in excellent yield and thus is a very practical method adaptable to large-scale synthesis. The detailed mechanistic aspects are studied and discussed.