Synthesis and biological properties of prodrugs of (S)-3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid

Eur J Med Chem. 2016 Jan 27:108:374-380. doi: 10.1016/j.ejmech.2015.12.009. Epub 2015 Dec 12.

Abstract

The lack of antiviral activity of recently described (S)-3-(adenin-9-yl)-2-(phosphonomethoxy)propanoic acid, or (S)-CPMEA in brief, has been speculated to possibly be due to the increased hydrophilicity of the molecule and, thus, by its limited cellular permeability. Efficient syntheses of novel lipophilic prodrugs of (S)-CPMEA masking either the carboxylic group or preferably both the phosphonate and carboxylic moieties, have been developed in order to increase bioavailability of the parent compound. Two prodrugs of (S)-CPMEA, namely phosphonate bis-amidate 15 and phenyloxy amidate 16, exhibited pan-genotypic anti-HCV activity at submicromolar concentrations.

Keywords: (S)-CPMEA; Acyclic nucleoside phosphonates; Antiviral; HCV; Prodrugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / pharmacology
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Hepacivirus / drug effects*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Organophosphonates
  • Prodrugs
  • diethyl 2,2'-(((((3-(adenin-9-yl)-1-methoxy-1-oxopropan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))bis(2-phenylpropanoate)
  • ethyl 3-(adenin-9-yl)-2-((((2-ethoxy-2-oxo-1-phenylethyl)amino)(phenoxy)phosphoryl)methoxy)propanoate
  • Adenine