Abstract
The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
© 2012 American Chemical Society
MeSH terms
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Administration, Oral
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Drug Resistance, Viral*
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepacivirus / genetics
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Hydrophobic and Hydrophilic Interactions
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Liver / metabolism
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Mutation
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Rats
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Replicon / drug effects
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacokinetics
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Serine Proteinase Inhibitors / pharmacology
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Structure-Activity Relationship
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / pharmacokinetics
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Urea / pharmacology
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / genetics
Substances
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Antiviral Agents
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NS3 protein, hepatitis C virus
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Serine Proteinase Inhibitors
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Viral Nonstructural Proteins
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Urea