Abstract
We report the synthesis and biological evaluation of a series of 4'-fluoro-2'- C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.
MeSH terms
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Alanine / analogs & derivatives*
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Alanine / chemical synthesis
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Alanine / pharmacology
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Animals
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Antiviral Agents / chemical synthesis
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Antiviral Agents / pharmacology*
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Cell Line, Tumor
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Dogs
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepatitis C / drug therapy
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Humans
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Nucleic Acid Synthesis Inhibitors / chemical synthesis
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Phosphoramides
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Prodrugs / chemical synthesis
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Prodrugs / pharmacology*
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Replicon / drug effects
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Uracil Nucleotides / chemical synthesis
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Uracil Nucleotides / metabolism
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Uracil Nucleotides / pharmacology*
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Uridine / analogs & derivatives*
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Uridine / chemical synthesis
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Uridine / pharmacology
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Viral Nonstructural Proteins / antagonists & inhibitors
Substances
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Antiviral Agents
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Nucleic Acid Synthesis Inhibitors
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Phosphoramides
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Prodrugs
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Uracil Nucleotides
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus
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Alanine
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adafosbuvir
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Uridine