The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1019-22. doi: 10.1016/j.bmcl.2011.11.127. Epub 2011 Dec 9.

Abstract

High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a ∼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.

MeSH terms

  • Administration, Oral
  • Animals
  • Crystallography, X-Ray
  • Dizocilpine Maleate / antagonists & inhibitors
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrazolones / administration & dosage
  • Pyrazolones / chemistry
  • Pyrazolones / pharmacology*
  • Quinolines / administration & dosage
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Rats
  • Schizophrenia / drug therapy*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrazolones
  • Quinolines
  • Dizocilpine Maleate
  • PDE10A protein, human
  • PDE10A protein, rat
  • Phosphoric Diester Hydrolases