title: Novel triple reuptake inhibitors with low risk of CAD associated liabilities: design, synthesis and biological activities of 4-[(1S)-1-(3,4-dichlorophenyl)-2-methoxyethyl]piperidine and related compounds.
abstract: A novel triple reuptake inhibitor with low potential of liabilities associated with cationic amphiphilic drug (CAD) was identified following an analysis of existing drugs. Low molecular weight (MW < ca. 300), low aromatic ring count (number = 1) and reduced lipophilicity (ClogP < 3.5) were hypothesized to be key factors to avoid the CAD associated liabilities (CYP2D6 inhibition, hERG inhibition and phospholipidosis). Based on the hypothesis, a series of piperidine compounds was designed with consideration of the common characteristic features of CNS drugs. Optimization of the side chain by adjusting overall lipophilicity suggested that incorporation of a methoxymethyl group could provide compounds with a balance of both potent reuptake inhibition and low liability potential. Compound (S)-3a showed a potent antidepressant-like effect in the mice tail suspension test (MED = 10 mg/kg, p.o.), proportional monoamine transporter occupancies and enhancement of monoamine concentrations in mouse prefrontal cortex.
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.forename: Eiji
authors.initials: E
authors.lastname: Kimura
authors.forename: Eiji
authors.initials: E
authors.lastname: Honda
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Terao
authors.forename: Atsuko
authors.initials: A
authors.lastname: Suzuki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kawai
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Arakawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohta
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Jun
authors.initials: J
authors.lastname: Terauchi
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D014179:Neurotransmitter Uptake Inhibitors; D010880:Piperidines; C032727:piperidine