基于结构的1,1 - 二氧代异噻唑和苯并[b]噻吩 - 1,1 - 二氧化物衍生物作为丙型肝炎病毒NS5B聚合酶新型抑制剂的设计、合成及生物学评价
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.
作者信息
Kim Sun Hee, Tran Martin T, Ruebsam Frank, Xiang Alan X, Ayida Benjamin, McGuire Helen, Ellis David, Blazel Julie, Tran Chinh V, Murphy Douglas E, Webber Stephen E, Zhou Yuefen, Shah Amit M, Tsan Mei, Showalter Richard E, Patel Rupal, Gobbi Alberto, LeBrun Laurie A, Bartkowski Darian M, Nolan Thomas G, Norris Daniel A, Sergeeva Maria V, Kirkovsky Leo, Zhao Qiang, Han Qing, 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 Jul 15;18(14):4181-5. doi: 10.1016/j.bmcl.2008.05.083. Epub 2008 May 24.
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) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.
设计、合成并评估了一系列新型的丙型肝炎病毒（HCV）NS5B聚合酶抑制剂，其包含1,1 - 二氧代异噻唑和苯并[b]噻吩 - 1,1 - 二氧化物。基于结构的设计指导下的构效关系（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1b型HCV聚合酶的IC(50)小于10nM，在细胞培养中对1b型复制子的EC(50)为70 nM。还评估了所选化合物的药物代谢动力学（DMPK）性质。
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