Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor

J Med Chem. 2009 Mar 26;52(6):1522-4. doi: 10.1021/jm900210d.

Abstract

In this communication, we report the discovery of 1S (apremilast), a novel potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-alpha inhibitor. The optimization of previously reported 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-(3,4-dimethoxyphenyl)propionic acid PDE4 inhibitors led to this series of sulfone analogues. Evaluation of the structure-activity relationship of substitutions on the phthalimide group led to the discovery of an acetylamino analogue 1S, which is currently in clinical trials.

MeSH terms

  • Administration, Oral
  • Animals
  • Drug Discovery*
  • Humans
  • Phosphodiesterase 4 Inhibitors*
  • Phosphodiesterase Inhibitors / administration & dosage
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thalidomide / administration & dosage
  • Thalidomide / analogs & derivatives*
  • Thalidomide / chemistry
  • Thalidomide / pharmacology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*

Substances

  • Phosphodiesterase 4 Inhibitors
  • Phosphodiesterase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Thalidomide
  • apremilast