Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists

Abstract G protein-coupled receptor 52 (GPR52) agonists are expected to improve the symptoms of psychiatric disorders. During exploration for a novel class of GPR52 agonists with good pharmacokinetic profiles, we synthesized 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1 H -1,2,4-triazol-1-yl)-2-methylbenzamide ( 4u ; half maximal effective concentration (EC 50 ) = 75 nM, maximal response (E max ) = 122%) starting from a high-throughput screening hit 3 (EC 50  = 470 nM, E max  = 56%). The structural features of a reported GPR52 agonist were applied to 3 , led to design 4-azolylbenzamides as novel GPR52 agonists. A structure–activity relationship study of 4-azolylbenzamide resulted in the design of the 1,2,4-triazole derivative 4u , which demonstrated excellent bioavailability in rats (F = 53.8%). Oral administration of 4u (10 mg/kg) significantly suppressed methamphetamine-induced hyperlocomotion in mice. Thus, 4u is a promising lead compound for drug discovery research of GPR52 agonists.