Abstract
A recently reported potent inhibitor of enterovirus 71 3C protease, ( R)-1, was found to have stability and potential toxicity issues due to the presence of a cyanohydrin moiety. Modifying the labile cyanohydrin moiety, by serendipity, led to the discovery of 4-iminooxazolidin-2-one-based inhibitors 4e and 4g with potent inhibitory activity and significantly improved stability. In vivo pharmacokinetic studies of 4e also demonstrated high plasma exposure and moderate half-life. These compounds have shown potential of becoming anti-EV71 drug candidates.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3C Viral Proteases
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Animals
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / metabolism
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Cysteine Proteinase Inhibitors / chemistry*
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Cysteine Proteinase Inhibitors / pharmacology*
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Enterovirus A, Human / enzymology*
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Male
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Mice
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Molecular Docking Simulation
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Nitriles / chemistry*
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Oxazoles / chemistry*
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Oxazoles / metabolism
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Oxazoles / pharmacology*
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Protein Conformation
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Viral Proteins / antagonists & inhibitors*
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Viral Proteins / chemistry
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Viral Proteins / metabolism
Substances
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Cysteine Proteinase Inhibitors
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Nitriles
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Oxazoles
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Viral Proteins
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cyanohydrin
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oxazolidine
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Cysteine Endopeptidases
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3C Viral Proteases