4-(1,1-Dioxo-1,4-dihydro-1 lambda super(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy- 2H-pyridazin-3-ones as potent inhibitors of HCV NS5B polymerase

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 16; pp. 4628 - 4632
• Main Authors: Ellis, David A, Blazel, Julie K, Webber, Stephen E, Tran, Chinh V, Dragovich, Peter S, Sun, Zhongxiang, Ruebsam, Frank, McGuire, Helen M, Xiang, Alan X, Zhao, Jingjing, Li, Lian-Sheng, Zhou, Yuefen, Han, Qing, Kissinger, Charles R, Showalter, Richard E, Lardy, Matthew, Shah, Amit M, Tsan, Mei, Patel, Rupal, LeBrun, Laurie A, Kamran, Ruhi, Bartkowski, Darian M, Nolan, Thomas G, Norris, Daniel A, Sergeeva, Maria V, Kirkovsky, Leo
• Format: Journal Article
• Language: English
• Published: 01.08.2008
• Subjects: Hepatitis C virus
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmcl.2008.07.014

4-(1,1-Dioxo-1,4-dihydro-1 lambda super(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy- 2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC sub(50) < 10 nM; 1b EC sub(50) = 1.1 nM) as well as good stability toward human liver microsomes (HLM t sub(1/2) > 60 min).