Design, synthesis, and anti-HIV activity of 4'-modified carbocyclic nucleoside phosphonate reverse transcriptase inhibitors

Bioorg Med Chem. 2009 Feb 15;17(4):1739-46. doi: 10.1016/j.bmc.2008.12.028. Epub 2008 Dec 24.

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

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Design
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / chemistry
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nucleosides / chemical synthesis*
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Nucleosides
  • Organophosphonates
  • Prodrugs
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase