You Youngsu, Kim Hee Sun, Bae Il Hak, Lee Seung Gi, Jee Min Hyeok, Keum Gyochang, Jang Sung Key, Kim B Moon
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea.
Eur J Med Chem. 2017 Jan 5;125:87-100. doi: 10.1016/j.ejmech.2016.09.031. Epub 2016 Sep 10.
The discovery of a new series of potent hepatitis C virus (HCV) NS5A inhibitors containing biaryl sulfone or sulfate cores is reported. Structure-activity relationship (SAR) studies on inhibitors containing various substitution patterns of the sulfate or sulfone core structure established that m-,m'- substituted biaryl sulfate core-based inhibitors containing an amide moiety (compound 20) or an imidazole moiety (compound 24) showed extremely high potency. Compound 20 demonstrated double-digit pM potencies against both genotype 1b (GT-1b) and 2a (GT-2a). Compound 24 also exhibited double-digit pM potencies against GT-1b and sub nM potencies against GT-2a. Furthermore, compounds 20 and 24 exhibited no cardiotoxicity in an hERG ligand binding assay and showed acceptable plasma stability and no mutagenic potential in the Ames test. In addition, these compounds showed distinctive additive effects in combination treatment with the NS5B targeting drug sofosbuvir (Sovaldi). The results of this study showed that the compounds 20 and 24 could be effective HCV inhibitors.
报道了一系列含有联芳基砜或硫酸酯核心的新型强效丙型肝炎病毒（HCV）NS5A抑制剂的发现。对含有硫酸酯或砜核心结构各种取代模式的抑制剂进行的构效关系（SAR）研究表明，含有酰胺部分（化合物20）或咪唑部分（化合物24）的间位、间'位取代的联芳基硫酸酯核心基抑制剂显示出极高的效力。化合物20对1b型基因型（GT-1b）和2a型基因型（GT-2a）均表现出两位数的pM效力。化合物24对GT-1b也表现出两位数的pM效力，对GT-2a表现出亚纳摩尔效力。此外，化合物20和24在hERG配体结合试验中未表现出心脏毒性，在Ames试验中显示出可接受的血浆稳定性且无致突变潜力。此外，这些化合物在与靶向NS5B的药物索磷布韦（Sovaldi）联合治疗中显示出独特的相加作用。本研究结果表明，化合物20和24可能是有效的HCV抑制剂。
