Abstract
A series of 2'-C-methyl branched purine and pyrimidine C-nucleosides were prepared. Their anti-HCV activity and pharmacological properties were profiled, and compared with known 2'-C-Me N-nucleoside counterparts. In particular, 2'-C-Me 4-aza-7,9-dideazaadenosine C-nucleoside (2) was found to have potent and selective anti-HCV activity in vitro as well as a favorable pharmacokinetic profile and in vivo potential for enhanced potency over the corresponding N-nucleoside.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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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Aza Compounds / chemical synthesis*
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Aza Compounds / pharmacokinetics
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Aza Compounds / pharmacology
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Cell Line
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Cricetinae
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Dogs
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepacivirus / growth & development
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Hepatocytes / drug effects
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Hepatocytes / virology
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Humans
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Injections, Intravenous
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Primary Cell Culture
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Purine Nucleosides / chemical synthesis*
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Purine Nucleosides / pharmacokinetics
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Purine Nucleosides / pharmacology
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Pyrimidine Nucleosides / chemical synthesis*
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Pyrimidine Nucleosides / pharmacokinetics
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Pyrimidine Nucleosides / pharmacology
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RNA-Dependent RNA Polymerase / antagonists & inhibitors*
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RNA-Dependent RNA Polymerase / metabolism
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Rats
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
Substances
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Antiviral Agents
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Aza Compounds
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Purine Nucleosides
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Pyrimidine Nucleosides
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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