From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: Indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons

被引：22

作者：

Beaulieu, Pierre L. ^{[1
]}

Gillard, James ^{[1
]}

Jolicoeur, Eric ^{[1
]}

Duan, Jianmin ^{[2
]}

Garneau, Michel ^{[2
]}

Kukolj, George ^{[2
]}

Poupart, Marc-Andre ^{[1
]}

机构：

[1] Boehringer Ingelheim Canada Ltd, Dept Chem, Res & Dev, Laval, PQ H7S 2G5, Canada

[2] Boehringer Ingelheim Canada Ltd, Dept Biol Sci, Res & Dev, Laval, PQ H7S 2G5, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 12期

关键词：

Hepatitis C virus; Antiviral; HCV; NS5B; Polymerase; Inhibitor; SAR; HEPATITIS-C; NONNUCLEOSIDE INHIBITORS; ALLOSTERIC INHIBITORS; HCVNS5B POLYMERASE; THERAPY;

D O I：

10.1016/j.bmcl.2011.04.059

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC50 <100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3658 / 3663

页数：6

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