Abstract
Optimization of benzimidazole 5-carboxamide derivatives previously identified as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) has led to the discovery of potent analogues that inhibit the enzyme at low-nanomolar concentrations. Greater than 800-fold improvement in potency from the original lead structure was achieved through the combined effects of conformational rigidification, molecular size extension and the identification of previously unexploited interactions. Furthermore, these inhibitors retain specificity for HCV polymerase relative to other viral and mammalian RNA polymerases.
MeSH terms
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Amides / chemistry*
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacology
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Cattle
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DNA-Directed RNA Polymerases / antagonists & inhibitors
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Hepacivirus / drug effects
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Hepacivirus / enzymology*
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Humans
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Molecular Structure
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Poliovirus / enzymology
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RNA-Dependent RNA Polymerase / antagonists & inhibitors
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
Substances
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Amides
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Antiviral Agents
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Benzimidazoles
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Enzyme Inhibitors
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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
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DNA-Directed RNA Polymerases