Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus

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• 作者：Matias Rey-Carrizo ; Marta Barniol-Xicota ; Chunlong Ma ; Marta Frigol茅-Vivas ; Eva Torres ; Lieve Naesens ; Salom茅 Llabr茅s ; Jordi Ju谩rez-Jim茅nez ; Francisco J. Luque ; William F. DeGrado ; Robert A. Lamb ; Lawrence H. Pinto ; Santiago V谩zquez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 10, 2014
• 年：2014
• 卷：57
• 期：13
• 页码：5738-5747
• 全文大小：411K
• ISSN：1520-4804

文摘

Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC₅₀, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.