The identification, and optimisation of hERG selectivity, of a mixed NET/SERT re-uptake inhibitor for the treatment of pain.
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.
Department of Pharmacology, MSD, Newhouse, Motherwell, ML1 5SH, United Kingdom.
Derek
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Angus
Matilda
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Bingham
Dawn
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Buchanan
Neil
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Dunbar
Linsday
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Gibson
Richard
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Goodwin
Anders
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Haunsø
Andrea
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Houghton
Margaret
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Huggett
Richard
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Morphy
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Napier
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Passmore
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Walker
D000818:Animals; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
D050483:Dopamine Plasma Membrane Transport Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011725:Pyridines; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014326:Tropanes