A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1456-61. doi: 10.1016/j.bmcl.2012.12.061. Epub 2012 Dec 22.

Abstract

A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Humans
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / metabolism
  • Neurotransmitter Uptake Inhibitors / pharmacology*
  • Norepinephrine / antagonists & inhibitors
  • Norepinephrine / chemistry
  • Norepinephrine / metabolism
  • Pain / drug therapy
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*
  • Rats
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Nerve Tissue Proteins
  • Neurotransmitter Uptake Inhibitors
  • Pyrrolidines
  • Serotonin Uptake Inhibitors
  • Norepinephrine