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

Derek Angus; Matilda Bingham; Dawn Buchanan; Neil Dunbar; Linsday Gibson; Richard Goodwin; Anders Haunsø; Andrea Houghton; Margaret Huggett; Richard Morphy; Susan Napier; Olaf Nimz; Joanna Passmore; Glenn Walker

doi:10.1016/j.bmcl.2010.11.021

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.

Authors

Derek Angus¹, Matilda Bingham, Dawn Buchanan, Neil Dunbar, Linsday Gibson, Richard Goodwin, Anders Haunsø, Andrea Houghton, Margaret Huggett, Richard Morphy, Susan Napier, Olaf Nimz, Joanna Passmore, Glenn Walker

Affiliation

¹ Department of Pharmacology, MSD, Newhouse, Motherwell, ML1 5SH, United Kingdom.

PMID: 21112782
DOI: 10.1016/j.bmcl.2010.11.021

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
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / chemistry*
Selective Serotonin Reuptake Inhibitors / therapeutic use
Serotonin Plasma Membrane Transport Proteins / chemistry*
Serotonin Plasma Membrane Transport Proteins / metabolism
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