The identification, and optimisation of hERG selectivity, of a mixed NET/SERT re-uptake inhibitor for the treatment of pain

Bioorg Med Chem Lett. 2011 Jan 1;21(1):271-5. doi: 10.1016/j.bmcl.2010.11.021. Epub 2010 Nov 6.

Abstract

Hit compound 1, a selective noradrenaline re-uptake transporter (NET) inhibitor was optimised to build in potency at the serotonin re-uptake transporter (SERT) whilst maintaining selectivity against the dopamine re-uptake transporter (DAT). During the optimisation of 1 it became clear that selectivity against the Kv11.1 potassium ion channel (hERG) was also a parameter for optimisation within the series. Discrete structural changes to the molecule as well as a lowering of global cLogP successfully increased the hERG selectivity to afford compound 11 m, which was efficacious in a mouse model of inflammatory pain, complete Freund's adjuvant (CFA) induced thermal hyperalgesia and a rat model of neuropathic pain, spinal nerve ligation (SNL) induced mechanical allodynia.

MeSH terms

  • Animals
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Male
  • Mice
  • Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Pain / drug therapy
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / therapeutic use
  • Rats
  • Rats, Wistar
  • Serotonin Plasma Membrane Transport Proteins / chemistry*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin Uptake Inhibitors / chemical synthesis
  • Serotonin Uptake Inhibitors / chemistry*
  • Serotonin Uptake Inhibitors / therapeutic use
  • Structure-Activity Relationship
  • Tropanes / chemical synthesis
  • Tropanes / chemistry*
  • Tropanes / therapeutic use

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Norepinephrine Plasma Membrane Transport Proteins
  • Pyridines
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Tropanes