Discovery and structure–activity relationships of novel selective norepinephrine and dual serotonin/norepinephrine reuptake inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2005-02, Vol.15 (3), p.699-703
• Main Authors: Boot, John, Cases, Manuel, Clark, Barry P., Findlay, Jeremy, Gallagher, Peter T., Hayhurst, Lorna, Man, Teresa, Montalbetti, Christian, Rathmell, Richard E., Rudyk, Hélène, Walter, Magnus W., Whatton, Maria, Wood, Virginia
• Format: Article
• Language: English
• Subjects: Adrenergic Uptake Inhibitors - chemical synthesis; Adrenergic Uptake Inhibitors - pharmacology; Biogenic Amines - antagonists & inhibitors; Biogenic Amines - metabolism; Biological and medical sciences; Dual reuptake inhibitor; Humans; Medical sciences; Miscellaneous; Monoamine reuptake inhibitors; Morpholines - chemical synthesis; Morpholines - pharmacology; Neuropharmacology; Norepinephrine; Norepinephrine - antagonists & inhibitors; Pharmacology. Drug treatments; SAR; Selective norepinephrine reuptake inhibitor; Serotonin; Serotonin Uptake Inhibitors - chemical synthesis; Serotonin Uptake Inhibitors - pharmacology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.11.025

The preparation of novel arylthiomethyl morpholines using a stereochemically versatile route featuring an aldol condensation as the key step is described. Members of this series are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. Novel arylthiomethyl morpholines are potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.