Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease

Eur J Med Chem. 2018 Apr 25:150:506-524. doi: 10.1016/j.ejmech.2018.03.005. Epub 2018 Mar 20.

Abstract

We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.

Keywords: Alzheimer; Dual inhibitors; HDAC6 selective; In-vivo test; PDE5 inhibition; Pharmacological tool compound; Tg2576 mice.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Cell Line
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Neuroglia / drug effects
  • Phosphodiesterase 5 Inhibitors / chemical synthesis
  • Phosphodiesterase 5 Inhibitors / chemistry
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Histone Deacetylase Inhibitors
  • Phosphodiesterase 5 Inhibitors
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • HDAC6 protein, human
  • Histone Deacetylase 6