title: Discovery of novel and selective tertiary alcohol containing inhibitors of the norepinephrine transporter.
abstract: A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.
authors.affiliation: Eli Lilly and Company, Ltd, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. cases_manuel@lilly.com
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Cases-Thomas
authors.forename: John J
authors.initials: JJ
authors.lastname: Masters
authors.forename: Magnus W
authors.initials: MW
authors.lastname: Walter
authors.forename: Gordon
authors.initials: G
authors.lastname: Campbell
authors.forename: Louise
authors.initials: L
authors.lastname: Haughton
authors.forename: Peter T
authors.initials: PT
authors.lastname: Gallagher
authors.forename: David R
authors.initials: DR
authors.lastname: Dobson
authors.forename: Vincent
authors.initials: V
authors.lastname: Mancuso
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonnier
authors.forename: Thierry
authors.initials: T
authors.lastname: Giard
authors.forename: Thierry
authors.initials: T
authors.lastname: Defrance
authors.forename: Michel
authors.initials: M
authors.lastname: Vanmarsenille
authors.forename: Andrew
authors.initials: A
authors.lastname: Ledgard
authors.forename: Craig
authors.initials: C
authors.lastname: White
authors.forename: Sivi
authors.initials: S
authors.lastname: Ouwerkerk-Mahadevan
authors.forename: Francoise J
authors.initials: FJ
authors.lastname: Brunelle
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Dezutter
authors.forename: Camy A
authors.initials: CA
authors.lastname: Herbots
authors.forename: Joel Y
authors.initials: JY
authors.lastname: Lienard
authors.forename: Jeremy
authors.initials: J
authors.lastname: Findlay
authors.forename: Lorna
authors.initials: L
authors.lastname: Hayhurst
authors.forename: John
authors.initials: J
authors.lastname: Boot
authors.forename: Linda K
authors.initials: LK
authors.lastname: Thompson
authors.forename: Susan
authors.initials: S
authors.lastname: Hemrick-Luecke
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D018360:Crystallography, X-Ray; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000438:Alcohols; D050483:Dopamine Plasma Membrane Transport Proteins; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins