1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: a new series of potent and selective triple reuptake inhibitors

J Med Chem. 2010 Mar 25;53(6):2534-51. doi: 10.1021/jm901818u.

Abstract

The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.

MeSH terms

  • Animals
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / pharmacokinetics
  • Azabicyclo Compounds / pharmacology*
  • Binding, Competitive
  • Biogenic Monoamines / metabolism
  • Biological Availability
  • Biological Transport / drug effects
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Microdialysis
  • Microsomes, Liver / metabolism
  • Models, Chemical
  • Molecular Structure
  • Motor Activity / drug effects
  • Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Prefrontal Cortex / metabolism
  • Rats
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Structure-Activity Relationship

Substances

  • Azabicyclo Compounds
  • Biogenic Monoamines
  • Cytochrome P-450 Enzyme Inhibitors
  • Dopamine Plasma Membrane Transport Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Cytochrome P-450 Enzyme System