Discovery of arylbenzylamines as PDE4 inhibitors with potential neuroprotective effect

Eur J Med Chem. 2019 Apr 15;168:221-231. doi: 10.1016/j.ejmech.2019.02.026. Epub 2019 Feb 11.

Abstract

Growing evidence confirms the potential of PDE4 inhibitors for the treatment of Parkinson's disease. Our reported PDE4 inhibitors FCPR16 and FCPR03 have displayed neuroprotective effects in SH-SY5Y cells, but have very low oral bioavailability. To access analogues with improved bioavailability, a new series of arylbenzylamine derivatives were designed and synthesized. Preliminary screening results of the series showed that arylbenzylamine derivatives bearing a pyridin-3-amine side chain displayed good inhibitory activities against human PDE4B1 and PDE4D7 isoforms. Moreover, kinetic studies revealed that the most potent compounds 11r and 11s with mid-nanomolar IC50 values partially bind to PDE4B1 (Imax = 93% and 90% respectively). Molecular docking results revealed the possible interactions of compounds 11r and 11s with upstream conserved region 2 (UCR2) of PDE4B1, which illuminate possible reasons for their partial inhibition against PDE4. Using a cell-based model of PD, compounds 11r and 11s were found to alleviate cellular apoptosis in SH-SY5Y cells induced by MPP+ (1-methyl-4-phenylpyridinium), with this neuroprotective effect being greater than PDE4 inhibitor rolipram. Furthermore, compound 11r displayed nearly sevenfold oral bioavailability (8.20%) than FCPR03 (1.23%).

Keywords: Design; Neuroprotective effect; Parkinson's disease; Phosphodiesterase-4 inhibitors; Synthesis.

MeSH terms

  • Animals
  • Benzylamines / chemical synthesis
  • Benzylamines / chemistry
  • Benzylamines / pharmacology*
  • Cell Survival / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Phosphodiesterase 4 Inhibitors / chemical synthesis
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Benzylamines
  • Neuroprotective Agents
  • Phosphodiesterase 4 Inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 4