Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors.

Abstract Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit ( 17 ) resulted in potent, selective, and brain penetrant 23 and 26 ; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3.