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.
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.
Middleton
Donald S
DS
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK. don.s.middleton@pfizer.com
Andrews
Mark
M
Glossop
Paul
P
Gymer
Geoffrey
G
Jessiman
Alan
A
Johnson
Patrick S
PS
Mackenny
Malcolm
M
Pitcher
Michael J
MJ
Rooker
Tony
T
Stobie
Alan
A
Tang
Kim
K
Morgan
Paul
P
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
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