Tang Guozhi, Lin Xianfeng, Qiu Zongxing, Li Wentao, Zhu Lei, Wang Lisha, Li Shaohua, Li Haodong, Lin Wenbin, Yang Mei, Guo Tao, Chen Li, Lee Daniel, Wu Jim Z, Yang Wengang
Roche R&D Center China , Shanghai, 201203, China.
WuXi Apptec Co., Ltd. , Shanghai, 200131, China.
ACS Med Chem Lett. 2011 Jun 7;2(8):603-7. doi: 10.1021/ml2000627. eCollection 2011 Aug 11.
Structural optimization of salicylamide-based hemagglutinin (HA) inhibitor 1 resulted in the identification of cis-3-(5-hydroxy-1,3,3-trimethylcyclohexylmethylamino)benzenesulfonamide 28 and its derivatives as potent anti-influenza agents. The lead compound 28 and its 2-chloro analogue 40 can effectively prevent cytopathic effects (CPE) caused by infection of influenza A/Weiss/43 strain (H1N1) with EC50 values of 210 and 86 nM, respectively. Mechanism of action studies indicate that 40 and its analogues inhibit the virus fusion with host endosome membrane by binding to HA and stabilizing the prefusion HA structure. With significantly improved metabolic stability, the reported series represents the first generation of orally bioavailable HA inhibitors that have a good selectivity window and potential for further development as novel anti-influenza agents.
基于水杨酰胺的血凝素（HA）抑制剂1的结构优化，得到了顺式-3-(5-羟基-1,3,3-三甲基环己基甲基氨基)苯磺酰胺28及其衍生物，它们是有效的抗流感药物。先导化合物28及其2-氯类似物40能有效预防甲型流感病毒/Weiss/43株（H1N1）感染引起的细胞病变效应（CPE），其半数有效浓度（EC50）值分别为210和86 nM。作用机制研究表明，40及其类似物通过与HA结合并稳定融合前HA结构来抑制病毒与宿主内体膜的融合。该系列化合物具有显著改善的代谢稳定性，代表了第一代具有良好选择性窗口且有潜力进一步开发为新型抗流感药物的口服生物利用度高的HA抑制剂。
