Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8. doi: 10.1016/j.bmcl.2012.07.072. Epub 2012 Jul 27.


We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.

MeSH terms

  • Administration, Oral
  • Animals
  • Cyclic GMP / analysis
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Phosphodiesterase Inhibitors / administration & dosage
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Phosphoric Diester Hydrolases / metabolism
  • Pyridines / administration & dosage
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Schizophrenia / drug therapy*
  • Structure-Activity Relationship


  • Phosphodiesterase Inhibitors
  • Pyridines
  • Pyrimidines
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases
  • Cyclic GMP