The discovery of aminopyrazines as novel, potent Nav1.7 antagonists: Hit-to-lead identification and SAR

Herein the discovery of a novel class of aminoheterocyclic Nav1.7 antagonists is reported. Hit compound 1 was potent but suffered from poor pharmacokinetics and selectivity. The compact structure of 1 offered a modular synthetic strategy towards a broad structure-activity relationship analysis. This analysis led to the identification of aminopyrazine 41, which had vastly improved hERG selectivity and pharmacokinetic properties.