1. The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia.
- Author
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Ho GD, Yang SW, Smotryski J, Bercovici A, Nechuta T, Smith EM, McElroy W, Tan Z, Tulshian D, McKittrick B, Greenlee WJ, Hruza A, Xiao L, Rindgen D, Mullins D, Guzzi M, Zhang X, Bleickardt C, and Hodgson R
- Subjects
- Administration, Oral, Animals, Crystallography, X-Ray, Dizocilpine Maleate antagonists & inhibitors, Dizocilpine Maleate pharmacology, Dose-Response Relationship, Drug, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors chemistry, High-Throughput Screening Assays, Humans, Models, Molecular, Molecular Structure, Pyrazolones administration & dosage, Pyrazolones chemistry, Quinolines administration & dosage, Quinolines chemistry, Rats, Stereoisomerism, Structure-Activity Relationship, Enzyme Inhibitors pharmacology, Phosphoric Diester Hydrolases metabolism, Pyrazolones pharmacology, Quinolines pharmacology, Schizophrenia drug therapy
- Abstract
High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a ∼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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