The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia.

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 3 mg/kg with an ED 50 of 4 mg/kg and displays a ∼6-fold separation between the ED 50 for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.