4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: design, synthesis and structure-activity relationships

  • Bioorg Med Chem Lett. 2009 May 15;19(10):2829-34. doi: 10.1016/j.bmcl.2009.03.090.
Paul V Fish  1 ,  Mark D Andrews ,  M Jonathan Fray ,  Alan Stobie ,  Florian Wakenhut ,  Gavin A Whitlock
Affiliations
  • 1. Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Kent, UK. [email protected]
PMID: 19359175 DOI: 10.1016/j.bmcl.2009.03.090
Abstract

Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.