title: Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: eiji.honda@takeda.com.
authors.forename: Eiji
authors.initials: E
authors.lastname: Honda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishichi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kimura
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshikawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Terao
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Arakawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Terauchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D001381:Azepines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C521289:1,4-diazepan-2-one; D000928:Antidepressive Agents; D001381:Azepines; D018765:Dopamine Uptake Inhibitors; D008024:Ligands
keywords: 1-Aryl-1,4-diazepan-2-one compounds; Antidepressant; Monoamine reuptake inhibition; Tail suspension test; Triple reuptake inhibition