Pyrazoloquinolines as PDE10A inhibitors: Discovery of a tool compound

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 3; pp. 1335 - 1339
• Main Authors: McElroy, William T., Tan, Zheng, Basu, Kallol, Yang, Shu-Wei, Smotryski, Jennifer, Ho, Ginny D., Tulshian, Deen, Greenlee, William J., Mullins, Deborra, Guzzi, Mario, Zhang, Xiaoping, Bleickardt, Carina, Hodgson, Robert
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.02.2012; Elsevier
• Subjects: Animals; Biological and medical sciences; chemistry; Drug Discovery; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Haplorhini; Hepatocytes - drug effects; Hepatocytes - metabolism; Inhibitory Concentration 50; Medical sciences; Molecular Structure; monkeys; PDE10A; Pharmacology. Drug treatments; Phosphodiesterase inhibitor; Phosphoric Diester Hydrolases - metabolism; Pyrazolones - chemical synthesis; Pyrazolones - chemistry; Pyrazolones - pharmacokinetics; Pyrazolones - pharmacology; quinoline; Quinolines; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacokinetics; Quinolines - pharmacology; Rats; rodents; Schizophrenia; Phosphodiesterase inhibitor; Schizophrenia; PDE10A; Psychosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.080

A series of pyrazoloquinolines, possessing (hetero)arylhydroxymethyl substituents at the quinoline C-4 position were evaluated as PDE10A inhibitors. Among these, methylpyrimidyl analogue 15 was identified as having good rodent and monkey exposure, and a MED of 10mg/kg in an in vivo model.