Benzothiophene derivatives as phosphodiesterase 10A (PDE10A) inhibitors: Hit-to-lead studies

Abstract A novel series of benzothiophene derivatives was discovered as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity relationship studies on high-throughput screening hit compound 1 led to the identification of 7-acetyl-3-methyl- N -(quinolin-2-yl)-1-benzothiophene-2-carboxamide ( 16 ), with potent inhibitory activity (PDE10A IC 50  = 7.6 nM) and selectivity (>1300-fold selectivity over the other tested phosphodiesterases). In addition, a novel methyl-induced conformational alteration of the benzothiophene-2-carboxamide derivatives is reported.