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

Abstract Herein the discovery of a novel class of aminoheterocyclic Na v 1.7 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.