6-（氮杂吲哚-2-基）吡啶-3-磺酰胺作为靶向丙型肝炎病毒NS4B的强效选择性抑制剂。
6-(Azaindol-2-yl)pyridine-3-sulfonamides as potent and selective inhibitors targeting hepatitis C virus NS4B.
作者信息
Chen Guangming, Ren Hongyu, Zhang Nanjing, Lennox William, Turpoff Anthony, Paget Steven, Li Chunshi, Almstead Neil, Njoroge F George, Gu Zhengxian, Graci Jason, Jung Stephen P, Colacino Joseph, Lahser Fred, Zhao Xin, Weetall Marla, Nomeir Amin, Karp Gary M
机构信息
PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
出版信息
Bioorg Med Chem Lett. 2015 Feb 15;25(4):781-6. doi: 10.1016/j.bmcl.2014.12.093. Epub 2015 Jan 7.
A structure-activity relationship investigation of various 6-(azaindol-2-yl)pyridine-3-sulfonamides using the HCV replicon cell culture assay led to the identification of a potent series of 7-azaindoles that target the hepatitis C virus NS4B. Compound 2ac, identified via further optimization of the series, has excellent potency against the HCV 1b replicon with an EC50 of 2nM and a selectivity index of >5000 with respect to cellular GAPDH RNA. Compound 2ac also has excellent oral plasma exposure levels in rats, dogs and monkeys and has a favorable liver to plasma distribution profile in rats.
使用丙型肝炎病毒（HCV）复制子细胞培养试验对各种6-（氮杂吲哚-2-基）吡啶-3-磺酰胺进行构效关系研究，从而鉴定出一系列靶向丙型肝炎病毒NS4B的强效7-氮杂吲哚。通过对该系列进行进一步优化鉴定出的化合物2ac，对HCV 1b复制子具有优异的活性，其半数有效浓度（EC50）为2nM，相对于细胞甘油醛-3-磷酸脱氢酶（GAPDH）RNA的选择性指数>5000。化合物2ac在大鼠、犬和猴中还具有优异的口服血浆暴露水平，并且在大鼠中具有良好的肝脏与血浆分布特征。
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