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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Characterization and structure-activity relationship study of iminodipyridinopyrimidines as novel hepatitis C virus inhibitor
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Characterization and structure-activity relationship study of iminodipyridinopyrimidines as novel hepatitis C virus inhibitor

机译：伊宁嘧啶嘧啶作为新型丙型肝炎病毒抑制剂的表征及结构 - 活性关系研究

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Abstract Upon high-throughput screening of synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified an iminodipyridinopyrimidine (IDPP) scaffold. IDPP did not inhibit HCV replication, but exhibited very potent inhibitory activity on early and late steps of HCV life cycle. Applying an intensive structure-activity relationship (SAR) study, a promising IDPP Lead compound ( 12c ) with excellent potency (EC 50 ?=?10?nM), high safety margin (SI?>?2000), and an acceptable stability in human and rat liver microsomes (t 1/2 >60?min) was identified. Overall, our results suggest that the IDPP scaffold could be used for the development of novel HCV interventions. Graphical abstract Display Omitted Highlights ? An iminodipyridinopyrimidine (IDPP) scaffold was identified by phenotypic HTS using infectious HCV. ? IDPP exhibited anti-HCV activity on early and late steps of the viral cycle, but not on HCV RNA replication. ? One IDPP derivative has a selectivity index >220,000 which is predestinated to conveniently study the HCV life cycle. ? Furthermore, a drugable IDPP lead compound was identified which could be developed to a therapeutic HCV intervention.
机译：摘要在高通量与感染丙型肝炎病毒的合成小分子文库的筛选（HCV）的细胞培养系统中，我们确定了一个iminodipyridinopyrimidine（IDPP）支架。 IDPP没有抑制丙肝病毒的复制，但对HCV生命周期的早期和晚期步骤表现出非常强的抑制活性。施加一个密集的结构 - 活性关系（SAR）研究中，有希望的IDPP铅化合物（12C）具有优良的效力（EC 50 =？10？纳米），高安全余量（SI？>？2000），并且在一个可接受的稳定性人和大鼠肝微粒体（吨1/2> 60？分钟）被鉴定。总的来说，我们的研究结果表明，IDPP支架可以用于新的HCV干预的发展。图形抽象显示省略了亮点？一个iminodipyridinopyrimidine（IDPP）支架的鉴定通过使用感染性HCV表型HTS。还是IDPP在病毒周期的早期和晚期步骤显示出抗HCV活性，但不能对HCV RNA复制。还是一个IDPP衍生物具有选择性指数> 22万，其预定他们方便地研究HCV生命周期。还是此外，可成药IDPP铅化合物被鉴定，其可以开发治疗HCV干预。

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