嘧啶核苷双前药和吡嗪核苷类化合物的发现：新型抗 HCV 药物。
Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides as novel anti-HCV agents.
机构信息
CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Topharman Shanghai Co., Ltd, No. 388 Jialilue Road, Zhangjiang Hitech Park, Shanghai 201203, China.
出版信息
Bioorg Med Chem. 2019 Mar 1;27(5):748-759. doi: 10.1016/j.bmc.2019.01.007. Epub 2019 Jan 16.
To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a-8c with similar EC values (0.20-0.22 μM) comparative to that of sofosbuvir (EC = 0.18 μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC = 7.3 μM) and S-29b (EC = 19.5 μM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents.
为探索双前药策略在抗 HCV 药物研发中的应用潜力，设计并合成了一系列在尿嘧啶环的 C4 位或 N3 位修饰的索非布韦衍生物。一些化合物表现出很强的抗 HCV 活性，如在基于基因型 1b 的复制子 Huh-7 细胞系中，化合物 4e 和 8a-8c 的 EC 值（0.20-0.22μM）与索非布韦（EC=0.18μM）相似。此外，化合物 8b 具有良好的人血浆稳定性，并可在人肝微粒体中预期地被代谢。另一方面，为了发现新型抗 HCV 核苷，我们研究了吡嗪-2(1H)-酮核苷及其磷酰胺酯前药。发现了一些活性化合物，如 25e（EC=7.3μM）和 S-29b（EC=19.5μM）。这类核苷很有趣，为抗病毒药物的开发开辟了新途径。
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