The identification, and optimisation of hERG selectivity, of a mixed NET/SERT re-uptake inhibitor for the treatment of pain |
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Authors: | Angus Derek Bingham Matilda Buchanan Dawn Dunbar Neil Gibson Linsday Goodwin Richard Haunsø Anders Houghton Andrea Huggett Margaret Morphy Richard Napier Susan Nimz Olaf Passmore Joanna Walker Glenn |
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Institution: | a Department of Medicinal Chemistry, MSD, Newhouse, Motherwell, ML1 5SH, United Kingdom b Department of Molecular Pharmacology, MSD, Newhouse, Motherwell, ML1 5SH, United Kingdom c Department of Pharmacology, MSD, Newhouse, Motherwell, ML1 5SH, United Kingdom |
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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 11m, 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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Keywords: | Noradrenaline re-uptake transporter inhibitor Serotonin re-uptake transporter inhibitor Monoamine re-uptake transporter inhibitor |
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