Smee D F, McKernan P A, Nord L D, Willis R C, Petrie C R, Riley T M, Revankar G R, Robins R K, Smith R A
Nucleic Acid Research Institute, Costa Mesa, California 92626.
Antimicrob Agents Chemother. 1987 Oct;31(10):1535-41. doi: 10.1128/AAC.31.10.1535.
A novel nucleoside analog, 4(5H)-oxo-1-beta-D- ribofuranosylpyrazolo[3,4-d]pyrimidine-3-thiocarboxamide (N10169), was evaluated in cell culture and in animals for antiviral activity against DNA and RNA viruses. The compound was highly active against strains of adeno-, vaccinia, influenza B, paramyxo-, picorna-, and reoviruses, with 50% inhibition of virus-induced cytopathology at 1 to 10 microM. Lesser or no antiviral effects were observed against herpes simplex, cytomegalo-, corona-, influenza A, vesicular stomatitis, and visna viruses. Drug potency against certain viruses was highly cell line dependent (N10169 was highly active in HeLa cells but was much less potent in Vero cells). This was correlated, in part, to differences in levels of adenosine kinase activity in these cell lines, since adenosine kinase appears to phosphorylate N10169 to its active form. N10169 was inhibitory to proliferating cells at antiviral concentrations, whereas stationary-phase monolayers tolerated higher concentrations (less than or equal to 100 microM). Exogenous uridine was able to reverse the virus-inhibitory effects of the compound, leading to the discovery that N10169 5'-monophosphate is a potent inhibitor of cellular orotidylate decarboxylase. N10169 was evaluated in mice that were infected intraperitoneally with banzi virus or inoculated intranasally with influenza B virus, and in hamsters that were infected intranasally with vaccinia virus. In each model, intraperitoneal injection of N10169 (100 to 300 mg/kg per day for 7 days) twice daily was ineffective, whereas intraperitoneal injection of ribavirin showed some benefit in the influenza B and banzi virus infection models.
一种新型核苷类似物，4(5H)-氧代-1-β-D-呋喃核糖基吡唑并[3,4-d]嘧啶-3-硫代甲酰胺（N10169），在细胞培养和动物实验中针对DNA和RNA病毒的抗病毒活性进行了评估。该化合物对腺病毒、痘苗病毒、乙型流感病毒、副粘病毒、小RNA病毒和呼肠孤病毒毒株具有高活性，在1至10微摩尔浓度下可抑制50%的病毒诱导细胞病变。对单纯疱疹病毒、巨细胞病毒、冠状病毒、甲型流感病毒、水疱性口炎病毒和维斯纳病毒观察到较小或无抗病毒作用。对某些病毒的药物效力高度依赖细胞系（N10169在HeLa细胞中活性高，但在Vero细胞中效力低得多）。这部分与这些细胞系中腺苷激酶活性水平的差异相关，因为腺苷激酶似乎将N10169磷酸化为其活性形式。N10169在抗病毒浓度下对增殖细胞有抑制作用，而静止期单层细胞能耐受更高浓度（小于或等于100微摩尔）。外源性尿苷能够逆转该化合物的病毒抑制作用，从而发现N10169 5'-单磷酸是细胞乳清酸脱羧酶的有效抑制剂。在经腹腔感染班齐病毒或经鼻接种乙型流感病毒的小鼠以及经鼻感染痘苗病毒的仓鼠中对N10169进行了评估。在每个模型中，每天两次腹腔注射N10169（100至300毫克/千克，共7天）无效，而腹腔注射利巴韦林在乙型流感病毒和班齐病毒感染模型中显示出一些益处。
