Synthesis and Structure-Activity Relationship Study of a New Series of Selective sigma(1) Receptor Ligands for the Treatment of Pain: 4-Aminotriazoles

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent s1 receptor (sigma R-1) ligands are reported. The compounds were prepared using a 4-5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the sigma R-1, and the selectivity over the sigma R-2 was improved on decreasing the central amine basicity. It was concluded that in order to achieve good sigma R-1 potency a minimum lipophilicity was required, while limiting to a defined range of cLogP avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound 13g exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character.