Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase

被引：32

作者：

Kim, Sun Hee ^{[1
]}

Tran, Martin T. ^{[1
]}

Ruebsam, Frank ^{[1
]}

Xiang, Alan X. ^{[1
]}

Ayida, Benjamin ^{[1
]}

McGuire, Helen ^{[1
]}

Ellis, David ^{[1
]}

Blazel, Julie ^{[1
]}

Tran, Chinh V. ^{[1
]}

Murphy, Douglas E. ^{[1
]}

Webber, Stephen E. ^{[1
]}

Zhou, Yuefen ^{[1
]}

Shah, Amit M. ^{[1
]}

Tsan, Mei ^{[1
]}

Showalter, Richard E. ^{[1
]}

Patel, Rupal ^{[1
]}

Gobbi, Alberto ^{[1
]}

LeBrun, Laurie A. ^{[1
]}

Bartkowski, Darian M. ^{[1
]}

Nolan, Thomas G. ^{[1
]}

Norris, Daniel A. ^{[1
]}

Sergeeva, Maria V. ^{[1
]}

Kirkovsky, Leo ^{[1
]}

Zhao, Qiang ^{[1
]}

Han, Qing ^{[1
]}

Kissinger, Charles R. ^{[1
]}

机构：

[1] Anadys Pharmaceut Inc, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 14期

关键词：

1,1-dioxoisothiazole; benzo[b]thiophene-1,1-dioxide; hepatitis C virus (HCV); NS5B inhibitors; X-ray co-crystal structures; DMPK properties;

D O I：

10.1016/j.bmcl.2008.05.083

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC50 values. The most potent compound exhibited IC50 less than 10 nM against the genotype 1b HCV polymerase and EC50 of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4181 / 4185

页数：5

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