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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein
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Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein

机译：靶向病毒NS4B蛋白为HCV复制抑制剂的设计与合成螺旋循环化合物

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摘要

Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5 nM and 1.2 nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9 nM and 6.1 nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's = 10.2 and 30.4 nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.
机译：设计，合成和评价其抗HCV活性，设计了两种新的螺旋环哌啶类似物的螺旋环哌啶类似物的螺旋环哌啶类似物。 提供了一系列哌啶ketals，得到了优异的体外抗HCV活性（EC50，抗基因型1A和1B复制品的EC50和1.2nm）。 一系列哌啶恶唑烷酮，得到27℃，其分别显示出EC50的10.9nm和6.1nm，分别对抗1A和1B复制品。 化合物6p和27c在体外直接与非结构Ns4b蛋白结合（分别为10.2和30.4nm）并在含有编码NS4B蛋白中的变化的耐受性突变的复制子中表现出降低的效力。

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    TaiV.W.-F.; GarridoD.; PriceD.J.; MaynardA.; PouliotJ.J.; XiongZ.; SealJ.W.; CreechK.L.; KrynL.H.; BaughmanT.M.; PeatA.J.;

  • 作者单位

    GlaxoSmithKline Antiviral Discovery Performance Unit 5 Moore Drive Research Triangle Park NC;

    GlaxoSmithKline Antiviral Discovery Performance Unit 5 Moore Drive Research Triangle Park NC;

    GlaxoSmithKline Platform Technology and Science 5 Moore Drive Research Triangle Park NC 27709;

    GlaxoSmithKline Platform Technology and Science 5 Moore Drive Research Triangle Park NC 27709;

    GlaxoSmithKline Antiviral Discovery Performance Unit 5 Moore Drive Research Triangle Park NC;

    GlaxoSmithKline Antiviral Discovery Performance Unit 5 Moore Drive Research Triangle Park NC;

    GlaxoSmithKline Platform Technology and Science 5 Moore Drive Research Triangle Park NC 27709;

    GlaxoSmithKline Platform Technology and Science 5 Moore Drive Research Triangle Park NC 27709;

    GlaxoSmithKline Platform Technology and Science 5 Moore Drive Research Triangle Park NC 27709;

    GlaxoSmithKline Anti Bacterial Discovery Performance Unit 5 Moore Drive Research Triangle Park;

    GlaxoSmithKline Antiviral Discovery Performance Unit 5 Moore Drive Research Triangle Park NC;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Hepatitis C virus (HCV); NS4B; Pyrazolo1; 5-apyridine; Replication inhibitors; Spirocyclic ketals;

    机译：丙型肝炎病毒（HCV）;NS4B;吡唑洛[1;5-A]吡啶;复制抑制剂;螺环防毒剂;

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