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

Abstract

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 are 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-methyl-imidazolidine-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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his 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)-5methyl-imidazolidine-2,4-dione derivatives (11-16). The drugability parameters: permeability,metabolic stability and safety,have been successfully evaluated.The experiments showed promising drung-like properties of all ligands, with special attention to compound 13 with the benzhydryl (diphenylmethyl)substituent.The forced sim test in mice has confirmed a good in vivo action of 13,showing its distinct antidepressant-like action

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