I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocycles

被引：46

作者：

Anilkumar, Gopinadhan N. ^{[1
]}

Lesburg, Charles A. ^{[1
]}

Selyutin, Oleg ^{[1
]}

Rosenblum, Stuart B. ^{[1
]}

Zeng, Qingbei ^{[1
]}

Jiang, Yueheng ^{[1
]}

Chan, Tin-Yau ^{[1
]}

Pu, Haiyan ^{[1
]}

Vaccaro, Henry ^{[1
]}

Wang, Li ^{[1
]}

Bennett, Frank ^{[1
]}

Chen, Kevin X. ^{[1
]}

Duca, Jose ^{[1
]}

Gavalas, Stephen ^{[1
]}

Huang, Yuhua ^{[1
]}

Pinto, Patrick ^{[1
]}

Sannigrahi, Mousumi ^{[1
]}

Velazquez, Francisco ^{[1
]}

Venkatraman, Srikanth ^{[1
]}

Vibulbhan, Bancha ^{[1
]}

Agrawal, Sony ^{[1
]}

Butkiewicz, Nancy ^{[1
]}

Feld, Boris ^{[1
]}

Ferrari, Eric ^{[1
]}

He, Zhiqing ^{[1
]}

Jiang, Chuan-kui ^{[1
]}

Palermo, Robert E. ^{[1
]}

Mcmonagle, Patricia ^{[1
]}

Huang, H. -C. ^{[1
]}

Shih, Neng-Yang ^{[1
]}

Njoroge, George ^{[1
]}

Kozlowski, Joseph A. ^{[1
]}

机构：

[1] Merck Res Labs, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 18期

关键词：

HCV; NS5B polymerase; HEPATITIS-C VIRUS; DEPENDENT RNA-POLYMERASE; CRYSTAL-STRUCTURE; INFECTION;

D O I：

10.1016/j.bmcl.2011.07.021

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50) = 0.9 mu M, replicon EC(50) > 100 mu M) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50) = 0.032 mu M, replicon EC(50) = 1.4 mu M) and 7r (NS5B IC(50) = 0.017 mu M, replicon EC(50) = 0.3 mu M) with improved enzyme and replicon activity. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：5336 / 5341

页数：6

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