Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists. Issue 12 (15th June 2017)

• Record Type: Journal Article
• Authors: Tokumaru, Kazuyuki; Ito, Yoshiteru; Nomura, Izumi; Nakahata, Takashi; Shimizu, Yuji; Kurimoto, Emi; Aoyama, Kazunobu; Aso, Kazuyoshi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 12(2017)
• Page Start: 3098
• Page End: 3115
• Publication Date: 2017-06-15
• Subjects: SAR structure–activity relationship -- cAMP 3′, 5′-cyclic adenosine monophosphate -- EC50 half maximal effective concentration -- MAP methamphetamine -- NMDA N-methyl-d-aspartate -- PK pharmacokinetic -- CHO Chinese hamster ovary -- SEM standard error of the mean -- AUC area under the curve; GPCR -- GRP52 agonist -- Methamphetamine-induced hyperlocomotion -- Metabolic stability -- 1, 2, 4-Triazole; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.03.064
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 (EC50 ) = 75 nM, maximal response (Emax ) = 122%) starting from a high-throughput screening hit3 (EC50 = 470 nM, Emax = 56%). The structural features of a reported GPR52 agonist were applied to3, 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 derivative4u, which demonstrated excellent bioavailability in rats (F = 53.8%). Oral administration of4u (10 mg/kg) significantly suppressed methamphetamine-induced hyperlocomotion in mice. Thus, 4u is a promising lead compound for drug discovery research of GPR52 agonists.