2,4-Diaminopyridine d-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 d-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.