title: 1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: a new series of potent and selective triple reuptake inhibitors.
abstract: The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy. Fabrizio.E.Micheli@gsk.com
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Micheli
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavanni
authors.forename: Roberto
authors.initials: R
authors.lastname: Arban
authors.forename: Roberto
authors.initials: R
authors.lastname: Benedetti
authors.forename: Barbara
authors.initials: B
authors.lastname: Bertani
authors.forename: Michela
authors.initials: M
authors.lastname: Bettati
authors.forename: Letizia
authors.initials: L
authors.lastname: Bettelini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bonanomi
authors.forename: Simone
authors.initials: S
authors.lastname: Braggio
authors.forename: Anna
authors.initials: A
authors.lastname: Checchia
authors.forename: Silvia
authors.initials: S
authors.lastname: Davalli
authors.forename: Romano
authors.initials: R
authors.lastname: Di Fabio
authors.forename: Elettra
authors.initials: E
authors.lastname: Fazzolari
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.forename: Carla
authors.initials: C
authors.lastname: Marchioro
authors.forename: Doug
authors.initials: D
authors.lastname: Minick
authors.forename: Michele
authors.initials: M
authors.lastname: Negri
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oliosi
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sartori
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tedesco
authors.forename: Luca
authors.initials: L
authors.lastname: Tarsi
authors.forename: Silvia
authors.initials: S
authors.lastname: Terreni
authors.forename: Filippo
authors.initials: F
authors.lastname: Visentini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zocchi
authors.forename: Laura
authors.initials: L
authors.lastname: Zonzini
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D015306:Biogenic Monoamines / Q000378:metabolism; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D017551:Microdialysis; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D053961:Azabicyclo Compounds; D015306:Biogenic Monoamines; D065607:Cytochrome P-450 Enzyme Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D003577:Cytochrome P-450 Enzyme System