Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase
作者:Sun Hee Kim、Martin T. Tran、Frank Ruebsam、Alan X. Xiang、Benjamin Ayida、Helen McGuire、David Ellis、Julie Blazel、Chinh V. Tran、Douglas E. Murphy、Stephen E. Webber、Yuefen Zhou、Amit M. Shah、Mei Tsan、Richard E. Showalter、Rupal Patel、Alberto Gobbi、Laurie A. LeBrun、Darian M. Bartkowski、Thomas G. Nolan、Daniel A. Norris、Maria V. Sergeeva、Leo Kirkovsky、Qiang Zhao、Qing Han、Charles R. Kissinger
DOI:10.1016/j.bmcl.2008.05.083
日期:2008.7
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50)
设计、合成和评估了一系列包含 1,1-二氧代异噻唑和苯并[b]噻吩-1,1-二氧化物的新型 HCV NS5B 聚合酶抑制剂。以基于结构的设计为指导的 SAR 研究导致鉴定出许多具有纳摩尔 IC(50) 值的强效 NS5B 抑制剂。最有效的化合物对基因型 1b HCV 聚合酶的 IC(50) 小于 10nM,对细胞培养中的基因型 1b 复制子的 EC(50) 为 70nM。还评估了所选化合物的 DMPK 特性。