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Chem Biol Drug Des. 2017 Dec;90(6):1295-1306. doi: 10.1111/cbdd.13106. Epub 2017 Oct 3.

In the search for a lead structure among series of potent and selective hydantoin 5-HT7 R agents: The drug-likeness in vitro study.

Author information

1
Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Kraków, Poland.
2
Department of Clinical Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
3
Department of Medicinal Chemistry Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.

Abstract

Since the year 1993, when 5-HT7 receptor (5-HT7 R) was discovered, there is no selective 5-HT7 R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5-HT7 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-HT7 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-HT7 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-HT7 receptor.

KEYWORDS:

5-HT7 receptor ligands; ADME-Tox parameters; antidepressant-like activity; arylpiperazines; drugability

PMID:
28886235
DOI:
10.1111/cbdd.13106
[Indexed for MEDLINE]

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