Pharmasset, Inc., East, Princeton, NJ 08540, USA.
Bioorg Med Chem Lett. 2010 Aug 1;20(15):4539-43. doi: 10.1016/j.bmcl.2010.06.025. Epub 2010 Jun 8.
Hepatitis C virus afflicts approximately 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clinical trials. As part of our continuing efforts to discover novel anti-HCV agents, 3',4'-oxetane cytidine and adenosine nucleosides were prepared as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as determined in a whole cell subgenomic replicon assay. However, 2'-mono/diflouro analogs, 4, 5, and 6 were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivatives were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates.
丙型肝炎病毒影响全球约 1.8 亿人，目前尚无直接作用的抗病毒药物可用于治疗这种疾病。我们的第一代核苷 HCV 抑制剂 RG7128 已经在临床上证明了其概念验证，目前正在进行 IIb 期临床试验。作为我们继续发现新型抗 HCV 药物的努力的一部分，3'，4'-氧杂环丁烷胞苷和腺苷核苷被制备为 HCV RNA 复制的抑制剂。在全细胞亚基因组复制子测定中，这些核苷被证明不是 HCV 的抑制剂。然而，2'-单/二氟类似物 4、5 和 6 很容易被脱氧胞苷激酶磷酸化为单磷酸代谢物，并且它们的三磷酸衍生物被证明是 HCV NS5B 聚合酶的抑制剂。在复制子测定中缺乏抗 HCV 活性可能是由于单磷酸无法转化为相应的二磷酸。
