Abstract
We synthesized bicyclic ether sialidase inhibitors such as tetrahydro-furan-2-yl, tetrahydro-pyran-2-yl, and oxepan-2-yl derivatives related to zanamivir. These compounds substituted by diol at the C-3' and C-4' positions resulted in the retention of low nanomolar inhibitory activities against not only influenza A virus sialidase but also influenza A virus in cell culture. Compound 11a in particular showed comparable efficacy in vivo relative to that of oseltamivir phosphate.
MeSH terms
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Administration, Oral
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / chemistry*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Ethers / chemistry
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Ethers / pharmacokinetics
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Ethers / pharmacology
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Guanidines
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Influenza A virus / drug effects
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Influenza A virus / enzymology
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Inhibitory Concentration 50
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Mice
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Models, Molecular
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Molecular Conformation
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Neuraminidase / antagonists & inhibitors*
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Orthomyxoviridae Infections / drug therapy*
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Pyrans
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Sialic Acids / chemistry*
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Sialic Acids / pharmacokinetics
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Sialic Acids / pharmacology
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Structure-Activity Relationship
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Zanamivir
Substances
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Antiviral Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Enzyme Inhibitors
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Ethers
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Guanidines
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Pyrans
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Sialic Acids
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Neuraminidase
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Zanamivir