Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).

Our development of PDE10Ainhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein(P-gp) efflux ratios in rat and human and poor metabolicstability. On the basis of cocrystalstructure of 1 in human PDE10Aenzyme, we designed a novel keto- benzimidazole26 with comparable PDE10Apotency devoid of efflux liabilities. On target in vivo coverage of PDE10Ain rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10Aat 30 mg/kg po and covered PDE10Areceptors in rat brain in a dose-dependent manner. Cocrystalstructure of 26 in PDE10Aconfirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto- benzimidazole34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.