文摘
A papaverine based pharmacophore model for PDE10Ainhibition was generated via SBDD and used to design a library of4-amino-6,7-dimethoxyquinazolines. From this library emerged an arylether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focalpoint for additional modeling, X-ray, and synthetic efforts towardincreasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selectivebrain penetrable inhibitor of PDE10A.