Discovery and Optimization of a 4-Aminopiperidine Scaffold for Inhibition of Hepatitis C Virus Assembly.
Discovery and Optimization of a 4-Aminopiperidine Scaffold for Inhibition of Hepatitis C Virus Assembly.
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DOI：
10.1021/acs.jmedchem.1c00696
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发表时间：
2021-07-08
影响因子：
7.3
通讯作者：
Marugan JJ
中科院分区：
文献类型：
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作者：
Rolt A;Talley DC;Park SB;Hu Z;Dulcey A;Ma C;Irvin P;Leek M;Wang AQ;Stachulski AV;Xu X;Southall N;Ferrer M;Liang TJ;Marugan JJ
大多数FDA批准的HCV治疗剂靶向病毒复制机制。一项自动化高通量表型筛选鉴定了几种小分子作为丙型肝炎病毒复制的有效抑制剂。在这里，我们公开了靶向HCV生命周期的组装阶段的4-氨基哌啶（4AP）支架的发现和优化。原始筛选命中（1）在HCVDNA试验中证明了有效性，但在病毒复制之前或期间未显示效价。共定位和感染性研究表明，4AP化学型抑制感染性HCV的组装和释放。化合物1与FDA批准的直接作用抗病毒化合物特拉匹韦和达卡他韦以及广谱抗病毒药物利巴韦林和环孢菌素A协同作用。在SAR活动之后，已经鉴定出4AP系列的几种衍生物具有增加的抗HCV效力、降低的体外毒性以及改善的体外和体内ADME性质。
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 anti-viral compounds Telaprevir and Daclatasvir, as well as broad spectrum anti-virals Ribavirin and cyclosporin A. Following an SAR campaign, several derivatives of the 4AP series have been identified with increased potency against HCV, reduced in vitro toxicity, as well as improved in vitro and in vivo ADME properties.