Discovery of Potent, Selective, and Orally Bioavailable Inhibitors against Phosphodiesterase-9, a Novel Target for the Treatment of Vascular Dementia

J Med Chem. 2019 Apr 25;62(8):4218-4224. doi: 10.1021/acs.jmedchem.8b01041. Epub 2019 Apr 3.

Abstract

To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism
  • Administration, Oral
  • Animals
  • Binding Sites
  • Catalytic Domain
  • Dementia, Vascular / drug therapy
  • Dementia, Vascular / pathology
  • Disease Models, Animal
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Maze Learning / drug effects
  • Mice
  • Molecular Docking Simulation
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Phosphodiesterase Inhibitors
  • Protein Isoforms
  • Pyrazoles
  • Pyridines
  • pyrazolopyridine
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • PDE9A protein, human