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.
Thomas A Chappie  1 ,  John M Humphrey ,  Martin P Allen ,  Kimberly G Estep ,  Carol B Fox ,  Lorraine A Lebel ,  Spiros Liras ,  Eric S Marr ,  Frank S Menniti ,  Jayvardhan Pandit ,  Christopher J Schmidt ,  Meihua Tu ,  Robert D Williams ,  Feng V Yang
Affiliations
  • 1. CNS Discovery and Experimental Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. [email protected]
PMID: 17228859 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.