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

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

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


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.

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