Discovery of a Series of 6,7-Dimethoxy-4-pyrrolidylquinazoline PDE10A Inhibitors

• Published in: Journal of medicinal chemistry Vol. 50; no. 2; pp. 182 - 185
• Main Authors: Chappie, Thomas A., Humphrey, John M., Allen, Martin P., Estep, Kimberly G., Fox, Carol B., Lebel, Lorraine A., Liras, Spiros, Marr, Eric S., Menniti, Frank S., Pandit, Jayvardhan, Schmidt, Christopher J., Tu, Meihua, Williams, Robert D., Yang, Feng V.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.01.2007; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Corpus Striatum - metabolism; Crystallography, X-Ray; Cyclic GMP - metabolism; Life Sciences & Biomedicine; Mice; Models, Molecular; Pharmacology & Pharmacy; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - metabolism; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Science & Technology; Structure-Activity Relationship; PHOSPHODIESTERASE PDE10A
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060653b

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.