Ferrocene-based inhibitors of hepatitis C virus replication that target NS5A with low picomolar in vitro antiviral activity

被引：12

作者：

Gadhachanda, Venkat R. ^{[1
]}

Eastman, Kyle J. ^{[1
]}

Wang, Qiuping ^{[1
]}

Phadke, Avinash S. ^{[1
]}

Patel, Dharaben ^{[1
]}

Yang, Wengang ^{[1
]}

Marlor, Christopher W. ^{[1
]}

Deshpande, Milind ^{[1
]}

Huang, Mingjun ^{[1
]}

Wiles, Jason A. ^{[1
]}

机构：

[1] Achillion Pharmaceut Inc, 300 George St, New Haven, CT 06511 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 21期

关键词：

Antiviral; Anti-infective; Bioorganometallic; HCV; Hepatitis; Infectious disease; NS5A; Organometallic; HCV NS5A; DISCOVERY; POTENT; DERIVATIVES; INFECTION; IODOFERROCENE; TOLERABILITY; PURIFICATION; DACLATASVIR; FERROQUINE;

D O I：

10.1016/j.bmcl.2018.09.023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1'-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.

引用

页码：3463 / 3471

页数：9

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