Design and synthesis of 4,5,6,7-tetrahydro-1H-1,2-diazepin-7-one derivatives as a new series of Phosphodiesterase 4 (PDE4) inhibitors

Bioorg Med Chem Lett. 2017 Jan 1;27(1):24-29. doi: 10.1016/j.bmcl.2016.11.040. Epub 2016 Nov 16.

Abstract

Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols. The resulting compounds demonstrated PDE4 inhibitory activity in cell free and cell-based assays comparable to the Zardaverine control used, suggesting potential avenues for their further development.

Keywords: Compound library; Diazepinone derivatives; PDE4 inhibitors; Phosphodiesterase 4.

MeSH terms

  • Azepines / chemical synthesis
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Molecular Structure
  • Phosphodiesterase 4 Inhibitors / chemical synthesis
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Azepines
  • Lipopolysaccharides
  • Phosphodiesterase 4 Inhibitors
  • Tumor Necrosis Factor-alpha
  • Cyclic Nucleotide Phosphodiesterases, Type 4