Design and synthesis of morpholine derivatives. SAR for dual serotonin & noradrenaline reuptake inhibition.
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.
Fish
Paul V
PV
Department of Genitourinary Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. paul.fish@pfizer.com
Deur
Christopher
C
Gan
Xinmin
X
Greene
Keri
K
Hoople
David
D
Mackenny
Malcolm
M
Para
Kimberly S
KS
Reeves
Keith
K
Ryckmans
Thomas
T
Stiff
Cory
C
Stobie
Alan
A
Wakenhut
Florian
F
Whitlock
Gavin A
GA
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
D009025:Morpholines; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C037574:morpholine