Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors

Abstract The Na V 1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over Na V 1.5 and good rat pharmacokinetics. Compound 18 , which demonstrated preferential inhibition of a slow inactivated state of Na V 1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat Na V 1.7 IC 50 it failed to demonstrate a robust reduction in nociceptive behavior.