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 |
| |
| Authors: | 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 |
| |
| Institution: | Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. |
| |
| Abstract: | 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. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ |
|
