title: 2,4-Diaminopyridine delta-opioid receptor agonists and their associated hERG pharmacology.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, CT13 9NJ, UK.
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.forename: Margarita
authors.initials: M
authors.lastname: Rodriguez-Lens
authors.forename: Martin D
authors.initials: MD
authors.lastname: Corless
authors.forename: Steven M
authors.initials: SM
authors.lastname: Gaulier
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Horne
authors.forename: Ross A
authors.initials: RA
authors.lastname: Kinloch
authors.forename: Graham N
authors.initials: GN
authors.lastname: Maw
authors.forename: David W
authors.initials: DW
authors.lastname: Pearce
authors.forename: Huw
authors.initials: H
authors.lastname: Rees
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Ringer
authors.forename: Thomas
authors.initials: T
authors.lastname: Ryckmans
authors.forename: Blanda L C
authors.initials: BL
authors.lastname: Stammen
mesh_terms: 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
chemical_list: 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