Designing rapid onset selective serotonin re-uptake inhibitors. Part 3: Site-directed metabolism as a strategy to avoid active circulating metabolites: structure-activity relationships of (thioalkyl)phenoxy benzylamines.
A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.
Middleton
Donald S
DS
Department of Discovery Chemistry (B500, IPC 324), Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. don.s.middleton@pfizer.com
Andrews
Mark
M
Glossop
Paul
P
Gymer
Geoffrey
G
Hepworth
David
D
Jessiman
Alan
A
Johnson
Patrick S
PS
MacKenny
Malcolm
M
Stobie
Alan
A
Tang
Kim
K
Morgan
Paul
P
Jones
Barry
B
D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D015394:Molecular Structure; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D001596:Benzylamines; D010647:Phenyl Ethers; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides