3-（1,1-二氧代-2H-（1,2,4）-苯并噻二嗪-3-基）-4-羟基-2（1H）-喹啉酮，丙型肝炎病毒RNA依赖性RNA聚合酶的强效抑制剂。
3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
作者信息
Tedesco Rosanna, Shaw Antony N, Bambal Ramesh, Chai Deping, Concha Nestor O, Darcy Michael G, Dhanak Dashyant, Fitch Duke M, Gates Adam, Gerhardt Warren G, Halegoua Dina L, Han Chao, Hofmann Glenn A, Johnston Victor K, Kaura Arun C, Liu Nannan, Keenan Richard M, Lin-Goerke Juili, Sarisky Robert T, Wiggall Kenneth J, Zimmerman Michael N, Duffy Kevin J
机构信息
Department of Medicinal Chemistry and Drug Metabolism, the Musculoskeletal, Microbial and Proliferative Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426, USA.
出版信息
J Med Chem. 2006 Feb 9;49(3):971-83. doi: 10.1021/jm050855s.
Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
最近，我们公布了一类通过对葛兰素史克公司专有化合物库进行高通量筛选（HTS）发现的新型丙型肝炎病毒（HCV）聚合酶抑制剂。这类有趣的3-(1,1-二氧代-2H-1,2,4-苯并噻二嗪-3-基)-4-羟基-2(1H)-喹啉酮能有效抑制HCV聚合酶的酶活性，并抑制亚基因组HCV复制子在Huh-7细胞中的复制能力。本报告将重点关注喹啉酮环上取代基的构效关系（SAR），最终发现了1-(2-环丙基乙基)-3-(1,1-二氧代-2H-1,2,4-苯并噻二嗪-3-基)-6-氟-4-羟基-2(1H)-喹啉酮（130），该抑制剂在生化和细胞试验中具有优异的效力，具有作为临床候选药物推进的吸引人的分子特性。还将讨论化合物130的开发潜力和安全性评估概况。
Zotero 插件