Di Francesco M Emilia, Avolio Salvatore, Dessole Gabriella, Koch Uwe, Pompei Marco, Pucci Vincenzo, Rowley Michael, Summa Vincenzo
Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, Pomezia, Italy.
Nucleosides Nucleotides Nucleic Acids. 2012;31(8):592-607. doi: 10.1080/15257770.2012.707344.
As part of an ongoing medicinal chemistry effort to identify novel nucleoside inhibitors of HCV NS5B polymerase, we report the discovery of a novel series of 2'-C-Methyl-ribose nucleoside derivatives bearing a 7-aryl and 7-heteroaryl- substituted 7-deaza-adenine nucleobase. A reliable platform for the synthesis and simplified purification of the corresponding nucleoside triphosphates (NTPs) was established, enabling a solid understanding of the SAR relationship within the series. By this approach, we identified the novel analogs 13a and 13b that demonstrated micromolar levels of cellular activity, and the NTPs of which, 16a and 16b, are excellent inhibitors of NS5B with IC(50) = 0.1 μM, a level of intrinsic potency similar to that of previous and current clinical candidates.
作为正在进行的寻找丙型肝炎病毒（HCV）NS5B聚合酶新型核苷抑制剂的药物化学研究工作的一部分，我们报告了一系列新型的2'-C-甲基核糖核苷衍生物的发现，这些衍生物带有7-芳基和7-杂芳基取代的7-脱氮腺嘌呤核苷碱基。建立了一个可靠的合成和简化相应核苷三磷酸（NTP）纯化的平台，从而能够深入了解该系列化合物的构效关系。通过这种方法，我们鉴定出了具有微摩尔水平细胞活性的新型类似物13a和13b，它们的NTP（16a和16b）是NS5B的优秀抑制剂，IC(50) = 0.1 μM，其内在活性水平与之前和当前的临床候选药物相当。
