Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities
Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities
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DOI：
10.1128/aac.45.3.743-748.2001
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发表时间：
2001-03-01
影响因子：
4.9
通讯作者：
Sidwell, RW
中科院分区：
文献类型：
--
作者：
Smee, DF;Huffman, JH;Sidwell, RW
已发现一系列新的环戊烷衍生物对流感病毒神经氨酸酶表现出有效的和选择性的抑制作用。这些化合物，命名为RWJ-270201、BCX-1827、BCX-1898和BCX-1923，与扎那米韦和奥司他韦羧酸盐平行测试，（H1 N1、H3 N2和H5 N1）和流感B病毒在MDCK细胞中的作用，使用通过视觉和中性红染料摄取确定的病毒细胞病变效应的抑制，测定50%有效（病毒抑制）浓度（EC 50）。新化合物对H1N1病毒A/拜仁/07/95、A/Beijing/262/95、A/PR/8/34和A/Texas/36/91的EC（50）（通过中性红测定法测定）小于或等于1.5 μ M。12株H3 N2和2株禽H5 N1病毒在< 0.3 μ M时被抑制，流感B/Beijing/184/93和B/Harbin/07/94病毒在< 0.2 μ M时被抑制，其它3株B病毒在0.8至8 μ M时被抑制。新的抑制剂在效力上与扎那米韦和奥司他韦羧酸盐相当（或略强于扎那米韦和奥司他韦羧酸盐）。在细胞增殖测定中，在浓度小于或等于ImM的化合物下未观察到细胞毒性。对选择用于临床开发的RWJ-270201的抗病毒活性进行了更详细的研究。其效力和奥司他韦羧酸盐的效力随着病毒感染复数的增加而降低。添加时间研究表明，为了获得最佳活性，需要在病毒暴露后开始0至12小时开始使用任一化合物进行处理。细胞暴露于RWJ-270201导致大部分病毒保持细胞缔合，细胞外病毒以浓度依赖性方式减少。这与其作为神经氨酸酶抑制剂的作用一致。RWJ-270201在治疗人流感病毒感染方面显示出前景。
A novel series of cyclopentane derivatives have been found to exhibit potent and selective inhibitory effects on influenza virus neuraminidase, These compounds, designated RWJ-270201, BCX-1827, BCX-1898, and BCX-1923, were tested in parallel with zanamivir and oseltamivir carboxylate against a spectrum of influenza A (H1N1, H3N2, and H5N1) and influenza B viruses in MDCK cells, inhibition of viral cytopathic effect ascertained visually and by neutral red dye uptake was used, with 50% effective (virus-inhibitory) concentrations (EC50) determined. Against the H1N1 viruses A/Bayern/07/95, A/Beijing/262/95, A/PR/8/34, and A/Texas/36/91, EC(50)s (determined by neutral red assay) of the novel compounds were less than or equal to 1.5 muM. Twelve strains of H3N2 and two strains of avian H5N1 viruses were inhibited at < 0.3 M Influenza B/Beijing/184/93 and B/Harbin/07/94 viruses were inhibited at < 0.2 M, with three other B virus strains inhibited at 0.8 to 8 muM, The novel inhibitors were comparable in potency to (or slightly more potent than) zanamivir and oseltamivir carboxylate. No cytotoxicity was seen with the compounds at concentrations of less than or equal to 1 mM in cell proliferation assays. The antiviral activity of RWJ-270201, chosen for clinical development, was studied in greater detail. Its potency and that of oseltamivir carboxylate decreased with increasing multiplicity of virus infection. Time-of-addition studies indicated that treatment with either compound needed to begin 0 to 12 h after virus exposure for optimal activity. Exposure of cells to RWJ-270201 caused most of the virus to remain cell associated, with extracellular virus decreasing in a concentration-dependent manner. This is consistent with its effect as a neuraminidase inhibitor. RWJ-270201 shows promise in the treatment of human influenza virus infections.