Novel HCVNS5B polymerase inhibitors derived from 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ6-benzo[1′,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2H-pyridazin-3-ones.: Part 5:: Exploration of pyridazinones containing 6-amino-substituents

被引：29

作者：

Dragovich, Peter S. ^{[1
]}

Blazel, Julie K. ^{[1
]}

Ellis, David A. ^{[1
]}

Han, Qing ^{[1
]}

Kamran, Ruhi ^{[1
]}

Kissinger, Charles R. ^{[1
]}

LeBrun, Laurie A. ^{[1
]}

Li, Lian-Sheng ^{[1
]}

Murphy, Douglas E. ^{[1
]}

Noble, Michael ^{[1
]}

Patel, Rupal A. ^{[1
]}

Ruebsam, Frank ^{[1
]}

Sergeeva, Maria V. ^{[1
]}

Shah, Amit M. ^{[1
]}

Showalter, Richard E. ^{[1
]}

Tran, Chinh V. ^{[1
]}

Tsan, Mei ^{[1
]}

Webber, Stephen E. ^{[1
]}

Kirkovsky, Leo ^{[1
]}

Zhou, Yuefen ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 20期

关键词：

pyridazinones; 5-hydroxy-3(2H)-pyridazinone derivatives; hepatitis C virus (HCV); RNA-dependent RNA polymerase (RdRp); non-nucleoside NS5B inhibitors;

D O I：

10.1016/j.bmcl.2008.08.094

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 < 0.10 mu M). In vitro DMPK data (microsome t(1/2), Caco-2 P-app) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：5635 / 5639

页数：5

共 31 条

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