Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Nav1.7 antagonists

Abstract Herein we describe the discovery, optimization, and structure–activity relationships of novel potent pyrrolopyrimidine Na v 1.7 antagonists. Hit-to-lead SAR studies of the pyrrolopyrimidine core, head, and tail groups of the molecule led to the identification of pyrrolopyrimidine 48 as exceptionally potent Na v 1.7 blocker with good selectivity over hERG and improved microsomal stability relative to our hit molecule and pyrazolopyrimidine 8 as a promising starting point for future optimization efforts.