Synthesis of 9-deoxo-4''-deoxy-6,9-epoxyerythromycin derivatives: novel and acid-stable motilides

J Med Chem. 1998 Aug 27;41(18):3402-8. doi: 10.1021/jm980022k.

Abstract

In our quest toward the discovery of highly potent and acid-stable motilides, novel 4"-deoxy derivatives of 9-deoxo-6, 9-epoxyerythromycin were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds, in their 9R configuration, were more potent than their 6,9-enol ether homologues in inducing well-coordinated smooth muscle contractions in an in vitro rabbit duodenal assay: e.g., (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethyl-6, 9-epoxyerythromycin A (10) and (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethanol-6, 9-epoxyerythromycin A (15) had a pED50 of 8.54 and 8.11 compared to a pED50 of 7.22 for compound 2 (ABT-229). Reduction of the 6,9-enol ether, which was aimed at improving the acid stability, afforded the most stable motilides to date with t1/2 of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC50 values of 8.52 and 8.70.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Drug Design
  • Drug Stability
  • Duodenum / drug effects
  • Duodenum / physiology
  • Erythromycin / analogs & derivatives*
  • Erythromycin / chemical synthesis
  • Erythromycin / chemistry
  • Erythromycin / metabolism
  • Erythromycin / pharmacology
  • Escherichia coli / drug effects
  • Hydrogen-Ion Concentration
  • In Vitro Techniques
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Pyloric Antrum / metabolism
  • Rabbits
  • Receptors, Gastrointestinal Hormone / metabolism
  • Receptors, Neuropeptide / metabolism
  • Staphylococcus aureus / drug effects
  • Stereoisomerism
  • Streptococcus / drug effects

Substances

  • 9-deoxo-4''-deoxy-3'-N--desmethyl-3'-N-ethanol-6,9-epoxyerythromycin A
  • 9-deoxo-4''-deoxy-3'-N-desmethyl-3'-ethyl-6,9-epoxyerythromycin A
  • Anti-Bacterial Agents
  • Receptors, Gastrointestinal Hormone
  • Receptors, Neuropeptide
  • motilin receptor
  • Erythromycin