title: Design and synthesis of reboxetine analogs morpholine derivatives as selective norepinephrine reuptake inhibitors.
abstract: As part of a discovery effort aimed at identifying novel norepinephrine reuptake inhibitors (NRIs), a number of substituted morpholines were designed and synthesized. The target compounds contain vicinal stereogenic centers, and the program was greatly facilitated by the adoption of efficient synthetic routes which allowed for the late stage incorporation of structural and physicochemical diversity into the targets. Structure-activity relationships were developed by optimizing individual ring components of the structure for NRI potency and for selectivity against other monoamine reuptake transporters. Several novel morpholine derivatives with a potent and selective NRI profile are described.
authors.affiliation: Department of Chemistry, Pfizer Global Research & Development Groton Laboratories, Ann Arbor, MI 48105, USA.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Xu
authors.forename: David L
authors.initials: DL
authors.lastname: Gray
authors.forename: Shelly A
authors.initials: SA
authors.lastname: Glase
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Barta
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007659:Ketones / Q000737:chemistry; D008956:Models, Chemical; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000077593:Reboxetine; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014050:Toluene / Q000737:chemistry
chemical_list: D018759:Adrenergic Uptake Inhibitors; D002491:Central Nervous System Agents; D007659:Ketones; D009025:Morpholines; D014050:Toluene; C037574:morpholine; D000077593:Reboxetine; D009638:Norepinephrine