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

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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.

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