Rey-Carrizo M et al. (2014), Easily accessible polycyclic amines that inhibi...

XB-ART-49748

J Med Chem 2014 Jul 10;5713:5738-47. doi: 10.1021/jm5005804.

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Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus.

Rey-Carrizo M , Barniol-Xicota M , Ma C , Frigolé-Vivas M , Torres E , Naesens L , Llabrés S , Juárez-Jiménez J , Luque FJ , DeGrado WF , Lamb RA , Pinto LH , Vázquez S .

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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.

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	Chart 1. Structures of Amt, Rmt, and Recently Developed Compounds with Potent Activity against A/M2-V27A Mutant Channelsaa.
	Scheme 1. Synthesis of Novel Polycyclic Pyrrolidine Derivatives
	Scheme 2. Synthesis of Compounds 18 and 19
	Figure 1. Representation of compound 18 bound to (left) the wild-type M2 channel and its V27A variant (down and up orientations shown in middle and right panels, respectively). The dashed line indicates the distance (Å) from the center-of-mass of the inhibitor to the plane formed by the Cα atoms of His37.
	Figure 2. Activity of the compounds in an influenza virus plaque reduction assay. MDCK cells were infected with influenza virus (strain A/HK/7/87; 25 PFU per well) in the presence of the test compounds (concentrations, from left to right: 0.5, 2, and 8 μM). After 72 h incubation, plaques were visualized by crystal violet staining. VC: mock-treated virus control. CC: uninfected cell control.