Abstract
We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP Deaminase / metabolism
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Amides / chemistry
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Amides / metabolism
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Cell Line, Tumor
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Drug Design
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Drug Evaluation, Preclinical
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Guanosine Monophosphate / analogs & derivatives*
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Guanosine Monophosphate / chemistry
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Guanosine Monophosphate / pharmacology
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Hepacivirus / drug effects*
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Hepacivirus / physiology
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Hepatitis C / drug therapy
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Humans
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Hydrolysis
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Inhibitory Concentration 50
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Microbial Sensitivity Tests
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Molecular Structure
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Nucleosides / chemical synthesis
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Nucleosides / chemistry
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Nucleosides / pharmacology
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Phosphoric Acids / chemistry
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Phosphoric Acids / metabolism
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Phosphorylation
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Prodrugs / chemical synthesis
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Prodrugs / chemistry*
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Prodrugs / metabolism
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Prodrugs / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
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Virus Replication / drug effects
Substances
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Amides
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Antiviral Agents
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IDX184
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Nucleosides
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Phosphoric Acids
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Prodrugs
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Guanosine Monophosphate
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phosphoramidic acid
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AMP Deaminase