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

  • Bioorg Med Chem Lett. 2008 Oct 1;18(19):5303-6. doi: 10.1016/j.bmcl.2008.08.040.
Donald S Middleton  1 ,  Mark Andrews ,  Paul Glossop ,  Geoffrey Gymer ,  David Hepworth ,  Alan Jessiman ,  Patrick S Johnson ,  Malcolm MacKenny ,  Alan Stobie ,  Kim Tang ,  Paul Morgan ,  Barry Jones
Affiliations
  • 1. Department of Discovery Chemistry (B500, IPC 324), Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. [email protected]
PMID: 18782666 DOI: 10.1016/j.bmcl.2008.08.040
Abstract

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.