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Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-13 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00561 Shanshan He 1 , Kelin Li 2 , Billy Lin 1 , Zongyi Hu 1 , Jingbo Xiao 3 , Xin Hu 3 , Amy Q. Wang 3 , Xin Xu 3 , Marc Ferrer 3 , Noel Southall 3 , Wei Zheng 3 , Jeffrey Aubé 2 , Frank J. Schoenen 2 , Juan J. Marugan 3 , T. Jake Liang 1 , Kevin J. Frankowski 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-13 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00561 Shanshan He 1 , Kelin Li 2 , Billy Lin 1 , Zongyi Hu 1 , Jingbo Xiao 3 , Xin Hu 3 , Amy Q. Wang 3 , Xin Xu 3 , Marc Ferrer 3 , Noel Southall 3 , Wei Zheng 3 , Jeffrey Aubé 2 , Frank J. Schoenen 2 , Juan J. Marugan 3 , T. Jake Liang 1 , Kevin J. Frankowski 2
Affiliation
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Reliance on hepatitis C virus (HCV) replicon systems and protein-based screening assays has led to treatments that target HCV viral replication proteins. The model does not encompass other viral replication cycle steps such as entry, processing, assembly and secretion, or viral host factors. We previously applied a phenotypic high-throughput screening platform based on an infectious HCV system and discovered an aryloxazole-based anti-HCV hit. Structure–activity relationship studies revealed several compounds exhibiting EC50 values below 100 nM. Lead compounds showed inhibition of the HCV pseudoparticle entry, suggesting a different mode of action from existing HCV drugs. Hit 7a and lead 7ii both showed synergistic effects in combination with existing HCV drugs. In vivo pharmacokinetics studies of 7ii showed high liver distribution and long half-life without obvious hepatotoxicity. The lead compounds are promising as preclinical candidates for the treatment of HCV infection and as molecular probes to study HCV pathogenesis.
中文翻译：
靶向丙型肝炎病毒抑制剂的芳恶唑类药物的开发，该抑制剂针对病毒复制周期的进入阶段
对丙型肝炎病毒（HCV）复制系统的依赖和基于蛋白质的筛选测定法导致了针对HCV病毒复制蛋白的治疗方法。该模型不包含其他病毒复制周期步骤，例如进入，加工，组装和分泌或病毒宿主因子。我们先前应用了基于感染性HCV系统的表型高通量筛选平台，并发现了基于芳基恶唑的抗HCV产品。结构-活性关系研究表明，几种化合物的EC 50值低于100 nM。铅化合物显示出对HCV假颗粒进入的抑制作用，表明与现有HCV药物的作用方式不同。命中7a并领先7ii与现有的HCV药物联合使用均显示出协同作用。7ii的体内药代动力学研究表明，肝脏分布高，半衰期长，没有明显的肝毒性。前导化合物有望作为治疗HCV感染的临床前候选药物，并有望成为研究HCV发病机理的分子探针。
更新日期：2017-07-14
中文翻译：
靶向丙型肝炎病毒抑制剂的芳恶唑类药物的开发，该抑制剂针对病毒复制周期的进入阶段
对丙型肝炎病毒（HCV）复制系统的依赖和基于蛋白质的筛选测定法导致了针对HCV病毒复制蛋白的治疗方法。该模型不包含其他病毒复制周期步骤，例如进入，加工，组装和分泌或病毒宿主因子。我们先前应用了基于感染性HCV系统的表型高通量筛选平台，并发现了基于芳基恶唑的抗HCV产品。结构-活性关系研究表明，几种化合物的EC 50值低于100 nM。铅化合物显示出对HCV假颗粒进入的抑制作用，表明与现有HCV药物的作用方式不同。命中7a并领先7ii与现有的HCV药物联合使用均显示出协同作用。7ii的体内药代动力学研究表明，肝脏分布高，半衰期长，没有明显的肝毒性。前导化合物有望作为治疗HCV感染的临床前候选药物，并有望成为研究HCV发病机理的分子探针。
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