Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, United States.
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
J Med Chem. 2021 Jul 8;64(13):9431-9443. doi: 10.1021/acs.jmedchem.1c00696. Epub 2021 Jun 29.
The majority of FDA-approved HCV therapeutics target the viral replicative machinery. An automated high-throughput phenotypic screen identified several small molecules as potent inhibitors of hepatitis C virus replication. Here, we disclose the discovery and optimization of a 4-aminopiperidine (4AP) scaffold targeting the assembly stages of the HCV life cycle. The original screening hit (1) demonstrates efficacy in the HCVcc assay but does not show potency prior to or during viral replication. Colocalization and infectivity studies indicate that the 4AP chemotype inhibits the assembly and release of infectious HCV. Compound 1 acts synergistically with FDA-approved direct-acting antiviral compounds Telaprevir and Daclatasvir, as well as broad spectrum antivirals Ribavirin and cyclosporin A. Following an SAR campaign, several derivatives of the 4AP series have been identified with increased potency against HCV, reduced toxicity, as well as improved and ADME properties.
大多数获得美国食品药品监督管理局批准的丙型肝炎治疗药物都针对病毒复制机制。一项自动化高通量表型筛选发现了几种小分子，它们是强效的丙型肝炎病毒复制抑制剂。在这里，我们公开了针对丙型肝炎病毒生命周期组装阶段的 4-氨基哌啶（4AP）支架的发现和优化。最初的筛选命中（1）在 HCVcc 测定中显示出疗效，但在病毒复制之前或期间没有显示出效力。共定位和感染性研究表明，4AP 类化合物抑制传染性丙型肝炎病毒的组装和释放。化合物 1 与美国食品药品监督管理局批准的直接作用抗病毒药物特拉匹韦和达拉他韦以及广谱抗病毒药物利巴韦林和环孢素 A 具有协同作用。在进行了一项 SAR 研究后，已经确定了几种 4AP 系列的衍生物，它们对丙型肝炎的活性增强，毒性降低，以及改善了 和 的 ADME 性质。
