Abstract
The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.
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 / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Hepacivirus / enzymology*
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Humans
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Macaca fascicularis
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Microsomes, Liver / metabolism
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Pyridones / chemical synthesis
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Pyridones / chemistry*
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Pyridones / pharmacology
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RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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RNA-Dependent RNA Polymerase / metabolism
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Structure-Activity Relationship
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Viral Nonstructural Proteins / metabolism*
Substances
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Antiviral Agents
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Enzyme Inhibitors
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Pyridones
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus
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RNA-Dependent RNA Polymerase