title: Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors.
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.
authors.affiliation: CNS Discovery and Experimental Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. thomas.a.chappie@pfizer.com
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Chappie
authors.forename: John M
authors.initials: JM
authors.lastname: Humphrey
authors.forename: Martin P
authors.initials: MP
authors.lastname: Allen
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Estep
authors.forename: Carol B
authors.initials: CB
authors.lastname: Fox
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Lebel
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.forename: Eric S
authors.initials: ES
authors.lastname: Marr
authors.forename: Frank S
authors.initials: FS
authors.lastname: Menniti
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.forename: Robert D
authors.initials: RD
authors.lastname: Williams
authors.forename: Feng V
authors.initials: FV
authors.lastname: Yang
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D011759:Pyrrolidines; D011799:Quinazolines; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP