Renin Inhibitors. III. Synthesis and Structure-Activity Relationships of Transition-State Inhibitors Containing Dihydroxyethylene Isostere at the P_1-P_<1'> Site
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概要
- 論文の詳細を見る
The design, synthesis and structure-activity relationships of transition-state inhibitors containing the dihydroxyethylene isostere at the scissile site are described. The compounds with (2S, 3R, 4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol at the P_1-P_<1'> site are potent renin inhibitors. (2S, 3R, 4S)-4-[N-[(2S)-3-Ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-L-norleucyl]amino-5-cyclohexyl-1-morpholino-2,3-pentanediol (2) (BW-175), which is the most potent inhibitor (IC_<50> : 3.3 nM against human renin) in this series, poorly inhibits cathepsin D (IC_<50> : 26000 nM) and pepsin (IC_<50> : >100000 nM), and thus it is specific for renin. Compound 2 contains only one amino acid and showed an oral bioavailability of 2.8% at 10 mg/kg and 9.7% at 30 mg/kg in rats. The interaction between renin and inhibitor 2 is discussed on the basis of molecular modeling studies.
- 公益社団法人日本薬学会の論文
- 1994-02-15
著者
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小池 隆
Structural Biology & Chemistry New Drug Discovery Research Laboratories Tsukuba Research Institu
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厚海 修吾
Structural Biology & Chemistry, New Drug Discovery Research Laboratories, Tsukuba Research Institute
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船橋 洋
Structural Biology & Chemistry, New Drug Discovery Research Laboratories, Tsukuba Research Institute
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中野 真人
Structural Biology & Chemistry, New Drug Discovery Research Laboratories, Tsukuba Research Institute
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田中 誠一
Structural Biology & Chemistry, New Drug Discovery Research Laboratories, Tsukuba Research Institute
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原田 純子
Structural Biology & Chemistry, New Drug Discovery Research Laboratories, Tsukuba Research Institute
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松山 研治
Biochemistry, New Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharamaceu
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池永 智美
Biochemistry, New Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceut
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森島 甫
Structural Biology & Chemistry, New Drug Discovery Research Laboratories, Tsukuba Research Institute
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松山 研治
Biochemistry New Drug Discovery Research Laboratories Tsukuba Research Institute Banyu Pharamaceutic
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船橋 洋
Structural Biology & Chemistry New Drug Discovery Research Laboratories Tsukuba Research Institu
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原田 純子
Structural Biology & Chemistry New Drug Discovery Research Laboratories Tsukuba Research Institu
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森島 甫
Structural Biology & Chemistry New Drug Discovery Research Laboratories Tsukuba Research Institu
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中野 真人
Structural Biology & Chemistry New Drug Discovery Research Laboratories Tsukuba Research Institu
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田中 誠一
Structural Biology & Chemistry New Drug Discovery Research Laboratories Tsukuba Research Institu
-
厚海 修吾
Structural Biology & Chemistry New Drug Discovery Research Laboratories Tsukuba Research Institu
-
池永 智美
Biochemistry New Drug Discovery Research Laboratories Tsukuba Research Institute Banyu Pharmaceutica
関連論文
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- Renin Inhibitors. III. Synthesis and Structure-Activity Relationships of Transition-State Inhibitors Containing Dihydroxyethylene Isostere at the P_1-P_ Site
- Renin Inhibitors. II. Synthesis and Structure-Activity Relationships of N-Terminus Modified Inhibitors Containing a Homostatine Analogue
- Renin Inhibitors. I. Synthesis and Structure-Activity Relationships of Transition-State Inhibitors Containing Homostatine Analogues at the Scissile Bond
- A New Approach to the Stereospecific Synthesis of a Dihydroxyehylene Isostere
- Novel Synthesis of a Dihydroxyethylene Isostere of Renin Inhibitors