2-Aminopyridines as Potent and Selective Na_v1.8 Inhibitors Exhibiting Efficacy in a Nonhuman Primate Pain Model

Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Na_v1.8 sodium channel. Parallel library synthesis, guided by in silico predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and in vivo efficacy of these compounds will be discussed.