Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.

Abstract In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b . Following further structure–activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35 , which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition.