Novel HCV NS5B 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 3: Further optimizatio

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• 作者：Lian-Sheng Li ; Yuefen Zhou ; Douglas E. Murphy ; Nebojsa Stankovic ; Jingjing Zhao ; Peter S. Dragovich ; Thomas Bertolini ; Zhongxiang Sun ; Benjamin Ayida ; Chinh V. Tran ; Frank Ruebsam ; Stephen E. Webber
• 关键词：Pyridazinones ; 5-Hydroxy-3(2H)-pyridazinone derivatives ; Hepatitis C virus (HCV) ; RNA-dependent RNA polymerase (RdRp) ; Small molecule ; Non-nucleoside NS5B inhibitors ; DMPK profiling ; Ratio of liver to plasma concentration
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 June 2008
• 卷：18
• 期：11
• 页码：3446-3455
• 文件大小：330 K

摘要

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC₅₀ (1b) < 10 nM; IC₅₀ (1a) = 22 nM; EC₅₀ (1b) = 5 nM], good stability toward human liver microsomes (HLM t_1/2 > 60 min), and high ratios of liver to plasma concentrations 12 h after a single oral administration to rats.