title: Designing rapid onset selective serotonin re-uptake inhibitors. Part 1: Structure-activity relationships of substituted (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine.
abstract: A series of sertraline analogues 4-39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced V(d) as a strategy to reduce T(max) and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced V(d) leading to significantly shorter T(max), in rat pharmacokinetic studies.
authors.affiliation: Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK. don.s.middleton@pfizer.com
authors.forename: Donald S
authors.initials: DS
authors.lastname: Middleton
authors.forename: Mark
authors.initials: M
authors.lastname: Andrews
authors.forename: Paul
authors.initials: P
authors.lastname: Glossop
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gymer
authors.forename: Alan
authors.initials: A
authors.lastname: Jessiman
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Johnson
authors.forename: Malcolm
authors.initials: M
authors.lastname: Mackenny
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pitcher
authors.forename: Tony
authors.initials: T
authors.lastname: Rooker
authors.forename: Alan
authors.initials: A
authors.lastname: Stobie
authors.forename: Kim
authors.initials: K
authors.lastname: Tang
authors.forename: Paul
authors.initials: P
authors.lastname: Morgan
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D018938:Caco-2 Cells; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D012039:Regional Blood Flow; D012680:Sensitivity and Specificity; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D009281:Naphthalenes; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C508857:(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine