Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors.
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.
Chappie
Thomas A
TA
CNS Discovery and Experimental Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. thomas.a.chappie@pfizer.com
Humphrey
John M
JM
Allen
Martin P
MP
Estep
Kimberly G
KG
Fox
Carol B
CB
Lebel
Lorraine A
LA
Liras
Spiros
S
Marr
Eric S
ES
Menniti
Frank S
FS
Pandit
Jayvardhan
J
Schmidt
Christopher J
CJ
Tu
Meihua
M
Williams
Robert D
RD
Yang
Feng V
FV
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
D010726:Phosphodiesterase Inhibitors; D011759:Pyrrolidines; D011799:Quinazolines; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP