2,4-Diaminopyridine delta-opioid receptor agonists and their associated hERG pharmacology.
A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective delta-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure-activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series.
Owen
Dafydd R
DR
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, CT13 9NJ, UK.
Rodriguez-Lens
Margarita
M
Corless
Martin D
MD
Gaulier
Steven M
SM
Horne
Valerie A
VA
Kinloch
Ross A
RA
Maw
Graham N
GN
Pearce
David W
DW
Rees
Huw
H
Ringer
Tracy J
TJ
Ryckmans
Thomas
T
Stammen
Blanda L C
BL
D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D004576:Electromyography / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D017465:Receptors, Opioid, delta; C026805:2,4-diaminopyridine; D015761:4-Aminopyridine