Dragovich Peter S, Blazel Julie K, Ellis David A, Han Qing, Kamran Ruhi, Kissinger Charles R, LeBrun Laurie A, Li Lian-Sheng, Murphy Douglas E, Noble Michael, Patel Rupal A, Ruebsam Frank, Sergeeva Maria V, Shah Amit M, Showalter Richard E, Tran Chinh V, Tsan Mei, Webber Stephen E, Kirkovsky Leo, Zhou Yuefen
Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2008 Oct 15;18(20):5635-9. doi: 10.1016/j.bmcl.2008.08.094. Epub 2008 Aug 29.
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
描述了作为丙型肝炎病毒RNA依赖性RNA聚合酶（NS5B）有效抑制剂的带有6-氨基取代基的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-酮的合成。其中几种试剂在细胞培养实验中也显示出强大的抗病毒活性（EC(50)<0.10 microM）。还公开了许多化合物的体外药物代谢动力学数据（微粒体t(1/2)，Caco-2 P(app)），并讨论了与NS5B蛋白复合的代表性抑制剂的晶体结构。
