title: Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.
abstract: Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
authors.affiliation: Department of Genitourinary Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. paul.fish@pfizer.com
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Christopher
authors.initials: C
authors.lastname: Deur
authors.forename: Xinmin
authors.initials: X
authors.lastname: Gan
authors.forename: Keri
authors.initials: K
authors.lastname: Greene
authors.forename: David
authors.initials: D
authors.lastname: Hoople
authors.forename: Malcolm
authors.initials: M
authors.lastname: Mackenny
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Para
authors.forename: Keith
authors.initials: K
authors.lastname: Reeves
authors.forename: Thomas
authors.initials: T
authors.lastname: Ryckmans
authors.forename: Cory
authors.initials: C
authors.lastname: Stiff
authors.forename: Alan
authors.initials: A
authors.lastname: Stobie
authors.forename: Florian
authors.initials: F
authors.lastname: Wakenhut
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Whitlock
mesh_terms: D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009025:Morpholines; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C037574:morpholine