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.
Subject(s)
4-Aminopyridine/analogs & derivatives , Chemistry, Pharmaceutical/methods , Ether-A-Go-Go Potassium Channels/chemistry , Receptors, Opioid, delta/agonists , 4-Aminopyridine/chemical synthesis , 4-Aminopyridine/pharmacology , Analgesics, Opioid/pharmacology , Animals , Cell Line , Combinatorial Chemistry Techniques , Drug Design , ERG1 Potassium Channel , Electromyography/methods , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Models, Chemical , Rats , Receptors, Opioid, delta/chemistry , Structure-Activity RelationshipABSTRACT
The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.
