Abstract
A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV reverse transcriptase (RT) (20, IC(50)=0.13 microM) has been discovered. In cell culture the parent phosphonate diacid 9 demonstrated antiviral activity EC(50)=16 microM, within two-fold of GS-9148, a prodrug of which is currently under clinical investigation, and within 5-fold of tenofovir (PMPA). In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148.
MeSH terms
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / pharmacology*
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Cell Line, Tumor
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Drug Design
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HIV Reverse Transcriptase / antagonists & inhibitors
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HIV Reverse Transcriptase / chemistry
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Humans
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Models, Molecular
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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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Organophosphonates / chemical synthesis*
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Organophosphonates / chemistry
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Organophosphonates / pharmacology
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Prodrugs / chemical synthesis
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / therapeutic use
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Structure-Activity Relationship
Substances
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Anti-HIV Agents
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Nucleosides
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Organophosphonates
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Prodrugs
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Reverse Transcriptase Inhibitors
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HIV Reverse Transcriptase