Design, synthesis, and evaluation of stable and taste-free erythromycin proprodrugs

J Med Chem. 2005 Jun 2;48(11):3878-84. doi: 10.1021/jm049155y.

Abstract

Erythromycin A is normally formulated for children as its 2'-ethyl succinate, a taste-free prodrug. Unfortunately, the prodrug hydrolyzes at a measurable rate in the medicine bottle, leading to the vile-tasting erythromycin. We have prepared derivatives of erythromycin B as putative paediatric prodrugs, taking advantage of the much improved acid stability of erythromycin B relative to erythromycin A. Thus, erythromycin B enol ether ethyl succinate is very poorly soluble in water, and its hydrolysis is undetectable in conditions resembling the medicine bottle. In acid, however, it converts rapidly to erythromycin B 2'-ethyl succinate, and this is in turn hydrolyzed to erythromycin B in neutral and basic conditions. Derivatives of erythromycin B enol ether are therefore proposed as taste-free proprodrugs of erythromycin B.

Publication types

  • Comparative Study

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Drug Stability
  • Erythromycin / analogs & derivatives*
  • Erythromycin / chemical synthesis*
  • Erythromycin / chemistry*
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Magnetic Resonance Imaging
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Solubility
  • Taste
  • Water

Substances

  • Anti-Bacterial Agents
  • Prodrugs
  • erythromycin B 2'-ethyl succinate
  • erythromycin B enol ether 2'-ethyl succinate
  • erythromycin B enol ethyl ether
  • Water
  • Erythromycin
  • berythromycin