Abstract
A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.
Keywords:
Antiviral; C-nucleoside; Hepatitis C; NS5B polymerase.
Copyright © 2017. Published by Elsevier Ltd.
MeSH terms
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Amides / chemistry
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Amides / pharmacokinetics
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Amides / pharmacology
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Animals
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Antiviral Agents / chemistry*
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology*
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Caco-2 Cells
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Cell Line
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Cricetinae
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Drug Discovery
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Drug Resistance, Viral
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Halogenation
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Hepacivirus / drug effects*
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Hepacivirus / genetics
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Hepacivirus / physiology
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Hepatitis C / drug therapy
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Humans
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Methylation
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Molecular Docking Simulation
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Nucleosides / chemistry*
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Nucleosides / pharmacokinetics
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Nucleosides / pharmacology*
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Phosphoric Acids / chemistry
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Phosphoric Acids / pharmacokinetics
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Phosphoric Acids / pharmacology
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Point Mutation
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Prodrugs / chemistry
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / metabolism
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Virus Replication / drug effects
Substances
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Amides
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Antiviral Agents
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Nucleosides
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Phosphoric Acids
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Prodrugs
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Viral Nonstructural Proteins
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phosphoramidic acid
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NS-5 protein, hepatitis C virus