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.
MeSH terms
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4-Aminopyridine / analogs & derivatives*
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4-Aminopyridine / chemical synthesis
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4-Aminopyridine / pharmacology
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Analgesics, Opioid / pharmacology
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Animals
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Cell Line
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Chemistry, Pharmaceutical / methods*
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Combinatorial Chemistry Techniques
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Drug Design
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ERG1 Potassium Channel
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Electromyography / methods
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Ether-A-Go-Go Potassium Channels / chemistry*
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Models, Chemical
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Rats
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Receptors, Opioid, delta / agonists*
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Receptors, Opioid, delta / chemistry
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Structure-Activity Relationship
Substances
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Analgesics, Opioid
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Receptors, Opioid, delta
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2,4-diaminopyridine
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4-Aminopyridine