Abstract
Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antiviral Agents / chemical synthesis
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Antiviral Agents / chemistry*
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Antiviral Agents / pharmacokinetics
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Benzofurans / chemistry
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacokinetics
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Furans / chemical synthesis
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Furans / chemistry*
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Furans / pharmacokinetics
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Half-Life
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Hepacivirus / enzymology*
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Liver / metabolism
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Pyrimidine Nucleosides / chemical synthesis
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Pyrimidine Nucleosides / chemistry*
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Pyrimidine Nucleosides / pharmacokinetics
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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RNA-Dependent RNA Polymerase / metabolism
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Rats
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Structure-Activity Relationship
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Benzofurans
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Enzyme Inhibitors
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Furans
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Pyrimidine Nucleosides
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Pyrimidines
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RNA-Dependent RNA Polymerase
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pyrimidine
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benzofuran