In the search for a lead structure among series of potent and selective hydantoin 5-HT7R agents: The drug-likeness in vitro study

Since the year 1993, when 5-HT7 receptor (5-HT7R) was discovered, there is no selective 5-HT7R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5-HT7R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by drug-likeness estimation of the first series of selective and potent 5-HT7R ligands among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-aryl-piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione derivatives (11-16). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test (FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2. The experiments showed promising drug-like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13. The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant-like activity in the FST. Taking into account the beneficial properties of 13, i.e., good drug-like parameters, the significant antagonistic action, high selectivity to 5-HT7R, and its in vivo antidepressant-like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5-HT7 receptor.