Abstract
A new class of the HCV NS5b RNA-dependent RNA polymerase inhibitors, the dihyroxypyrimidinecarboxylic acid derivative, was designed from a diketoacid and meconic acid derivative discovered by screening. Mechanism of action and essential moieties required for activity were identified. The corresponding N-methylpyrimidinone was also prepared; both classes are novel, reversible, and selective inhibitors of the HCV NS5b polymerase with improved druglike characteristics.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Drug Design
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Hepacivirus / enzymology
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In Vitro Techniques
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Isomerism
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Keto Acids / chemical synthesis*
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Keto Acids / chemistry
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Keto Acids / pharmacology
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Microsomes, Liver / metabolism
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Models, Molecular
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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RNA-Dependent RNA Polymerase / chemistry
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Rats
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Structure-Activity Relationship
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Viral Nonstructural Proteins / metabolism*
Substances
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Keto Acids
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Pyrimidines
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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