Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors

J Med Chem. 2007 Jan 25;50(2):182-5. doi: 10.1021/jm060653b.

Abstract

A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A.

MeSH terms

  • Animals
  • Corpus Striatum / metabolism
  • Crystallography, X-Ray
  • Cyclic GMP / metabolism
  • Mice
  • Models, Molecular
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Structure-Activity Relationship

Substances

  • Phosphodiesterase Inhibitors
  • Pyrrolidines
  • Quinazolines
  • Pde10a protein, mouse
  • Phosphoric Diester Hydrolases
  • Cyclic GMP

Associated data

  • PDB/208H