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

[Display omitted] •Novel PDE10 inhibitors.•Optimization supported by X-ray crystal structure analysis and molecular modeling.•Potent, selective, and brain penetrant.•Improved PK profile (rat): lower clearance in vivo and decreased volume of distribution (compared to WEB-3). 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.