Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition

Abstract A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1 H -pyrazol-3-yl]oxy}methyl)phenyl]quinoline ( 1 ). Replacement of pyridine ring of 1 with N -methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1 H -pyrazol-4-yl)pyridin-2(1 H )-one ( 42b ), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with 11 C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED 50 value of 2.0 mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3 mg/kg in mice novel object recognition test.