Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (16), p.3898-3902
• Main Authors: Honda, Eiji, Ishichi, Yuji, Kimura, Eiji, Yoshikawa, Masato, Kanzaki, Naoyuki, Nakagawa, Hideyuki, Terao, Yasuko, Suzuki, Atsuko, Kawai, Takayuki, Arakawa, Yuuichi, Ohta, Hiroyuki, Terauchi, Jun
• Format: Article
• Language: English
• Subjects: 1-Aryl-1,4-diazepan-2-one compounds; Administration, Oral; Animals; Antidepressant; Antidepressive Agents - administration & dosage; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacology; Azepines - administration & dosage; Azepines - chemistry; Azepines - pharmacology; Depression - drug therapy; Dopamine Uptake Inhibitors - administration & dosage; Dopamine Uptake Inhibitors - chemical synthesis; Dopamine Uptake Inhibitors - pharmacology; Dose-Response Relationship, Drug; Drug Design; Humans; Ligands; Mice; Molecular Structure; Monoamine reuptake inhibition; Motor Activity - drug effects; Structure-Activity Relationship; Tail suspension test; Triple reuptake inhibition
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.06.046

[Display omitted] A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.