State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu chong zhi Road, Shanghai 201203, China.
J Med Chem. 2013 Feb 14;56(3):671-84. doi: 10.1021/jm3009713. Epub 2013 Jan 30.
In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC(50) value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC(50) = 0.0014 μM, H5N1 IC(50) = 0.012 μM, H1N1 IC(50) = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t(1/2)) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.
为了利用神经氨酸酶活性部位的 430 个腔，合成了 22 种 C-1 和 C-4 修饰的扎那米韦类似物，并测定了它们对 1 组（H5N1、H1N1）和 2 组（H3N2）神经氨酸酶的抑制活性。化合物 9f 表现出最强的效力，对 H3N2、H5N1 和 H1N1 的 IC50 值分别为 0.013、0.001 和 0.09 μM，与扎那米韦（H3N2 IC50 = 0.0014 μM、H5N1 IC50 = 0.012 μM、H1N1 IC50 = 0.001 μM）相似。化合物 9f 在大鼠中的药代动力学研究表明，与扎那米韦（po 剂量）相比，其血浆半衰期（t1/2）长得多。分子建模提供了关于新抑制剂与神经氨酸酶之间结合模型的信息，C-1 位的伸长基团朝向 430 环区域。这项研究可能代表了未来开发改良抗流感药物的新起点。
