In the search for a lead structure among series of potent and selective hydantoin 5‐ HT 7 R agents: The drug‐likeness in vitro study

Since the year 1993, when 5‐ HT 7 receptor (5‐ HT 7 R) was discovered, there is no selective 5‐ HT 7 R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5‐ HT 7 R 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‐ HT 7 R 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‐ HT 7 R, 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‐ HT 7 receptor.