2. Academic Validation
  3. Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors

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

Affiliation

  • 1 CNS Discovery and Experimental Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. thomas.a.chappie@pfizer.com
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.

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