3-Azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives: From Wild-Type Inhibitors of the M2 Ion Channel of Influenza A Virus to Derivatives with Potent Activity against the V27A Mu

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• 作者：Matias Rey-Carrizo ; Eva Torres ; Chunlong Ma ; Marta Barniol-Xicota ; Jun Wang ; Yibing Wu ; Lieve Naesens ; William F. DeGrado ; Robert A. Lamb ; Lawrence H. Pinto ; Santiago V谩zquez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9265-9274
• 全文大小：359K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1^5,8.0^1,5]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC₅₀. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.