Synthesis and in vivo evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors.
A novel class of phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability in mouse liver microsomes were designed and synthesized starting from 2-(4-1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-ylphenoxymethyl)quinoline (MP-10). Replacement of the phenoxymethyl part of MP-10 with an oxymethyl phenyl unit led to the identification of 2-4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yloxymethyl)phenylquinoline (14), which showed moderate PDE10A inhibitory activity with improved metabolic stability in mouse and human liver microsomes over MP-10. Compound 14 showed high concentrations in plasma and brain after intraperitoneal administration and dose-dependently attenuated the hyperlocomotion induced by phencyclidine in mice, and oral administration of 14 (0.1, 0.3 mgkg) also improved visual-recognition memory impairment in mice.