Studies on 5-Lipoxygenase Inhibitors. II. Discovery, Optical Resolution and Enantioselective Synthesis of FR110302,a Highly Potent Non-redox Type-5-Lipoxygenase Inhibitor
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概要
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A novel series of 2,2-dialkyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphthols was synthesized and evaluated as 5-lipoxygenase (5-LO) inhibitors. Systematic optimization led to identification of several highly potent non-redox type 5-LO inhibitors with nanomolar IC_<50>s as racemic mixtures. Optical resolution of racemate 50 indicated that its 5-LO inhibitory activity was enantiospecific and due to the (+)-enantiomer. An efficient synthetic route to the (+)-enantiomers via asymmetric reduction of tetralone intermediates was established. The best compound, (+)-2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphthol (FR110302,(+)-50), showed potent inhibitory activity against leukotriene (LT) biosynthesis by intact neutrophiles in rats (IC_<50> 4.9nM) and in humans (IC_<50> 40 nM). Furthermore oral administration of FR110302 significantly inhibited neutrophil migration in the rat air pouch model at 1 mg/kg.
- 公益社団法人日本薬学会の論文
- 1998-10-15
著者
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Tanaka H
Faculty Of Pharmacy Meijo University
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TANAKA Hirokazu
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.
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Oku Teruaki
Department Of Microbiology Hoshi University School Of Pharmacy And Pharmaceutical Sciences
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Oku Teruaki
Department Of Microbiology School Of Pharmacy Hoshi University
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Toyama Hirohide
Institute For Chemical Research Kyoto University
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Tanaka Haruyuki
Chemical Branch Faculty Of Engineering And Kansai University High Technology Research Center Kansai
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Kayakiri H
Medicinal Chemistry Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Oku T
Amagasaki Chemical Industries Co.
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Kawai Yoshio
Faculty Of Life Sciences Toyo University
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YATABE Takumi
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.,
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KAYAKIRI Hiroshi
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.,
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KAWAI Yoshio
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.,
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OKU Teruo
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.,
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Yatabe Takumi
Exploratory Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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Tanaka Hirokazu
Exploratory Research Laboratories Fujisawa Pharmaceutical Co. Ltd.
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TANAKA Hiromi
Department of Physics Faculty of Education, Saga University
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