Novel N-acyl-carbazole derivatives as 5-HT7R antagonists

作者：Kim Youngjae; Yeom Miyoung; Tae Jinsung; Rhim Hyewhon; Choo Hyunah^*

来源：European Journal of Medicinal Chemistry, 2016, 110: 302-310.

DOI：10.1016/j.ejmech.2016.01.043

• 5-HT7R
• Antagonist
• N-Acyl-carbazole
• Serotonin
• Depression
• GPCR

To discover a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT7R. Among total 30 compounds synthesized, four compounds 27-30 showed good binding affinities with K-i values of <100 nM. The compound 28, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT7R antagonist following functional assays. The compound 28 showed moderate activity on hERG channel and good stability in microsomal stability test. The compound 28 exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound 28 was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT7R antagonist 28 can be considered as a good lead for discovery of novel 5HT(7)R antagonists as antidepressants.

• 出版日期2016-3-3