Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine as selective noradrenaline reuptake inhibitors: Reducing P-gp mediated efflux by modulation of H-bond acceptor capacity

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4355-9. doi: 10.1016/j.bmcl.2008.06.071. Epub 2008 Jun 25.

Abstract

Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration.

MeSH terms

  • Animals
  • Central Nervous System / drug effects
  • Combinatorial Chemistry Techniques
  • Humans
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Rats
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis*
  • Selective Serotonin Reuptake Inhibitors / chemistry
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Stereoisomerism

Substances

  • PF-3609113
  • Pyrrolidines
  • Serotonin Uptake Inhibitors