源自4-(1',1'-二氧代-1',4'-二氢-1'λ(6)-苯并[1',2',4']噻二嗪-3'-基)-5-羟基-2H-哒嗪-3-酮的新型丙型肝炎病毒NS5B聚合酶抑制剂。第3部分：2-、6-和7'-取代基的进一步优化及初步药代动力学评估。
Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments.
作者信息
Li Lian-Sheng, Zhou Yuefen, Murphy Douglas E, Stankovic Nebojsa, Zhao Jingjing, Dragovich Peter S, Bertolini Thomas, Sun Zhongxiang, Ayida Benjamin, Tran Chinh V, Ruebsam Frank, Webber Stephen E, Shah Amit M, Tsan Mei, Showalter Richard E, Patel Rupal, Lebrun Laurie A, Bartkowski Darian M, Nolan Thomas G, Norris Daniel A, Kamran Ruhi, Brooks Jennifer, Sergeeva Maria V, Kirkovsky Leo, Zhao Qiang, Kissinger Charles R
机构信息
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
出版信息
Bioorg Med Chem Lett. 2008 Jun 1;18(11):3446-55. doi: 10.1016/j.bmcl.2008.02.072. Epub 2008 Mar 5.
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 [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.
研究了5-羟基-3(2H)-哒嗪酮衍生物作为1型丙型肝炎病毒NS5B聚合酶抑制剂的情况。先导化合物优化导致发现了化合物3a，其在生化和复制子试验中表现出强效抑制活性[IC(50)(1b)<10 nM；IC(50)(1a)=22 nM；EC(50)(1b)=5 nM]，对人肝微粒体具有良好的稳定性(HLM t(1/2)>60分钟)，并且在对大鼠单次口服给药12小时后肝与血浆浓度的比值较高。
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