Development and characterization of pyridyl carboxamides as potent and highly selective Nav1.8 inhibitors

The voltage-gated sodium channel Na_v1.8 (SCN10A) has strong genetic and pharmacological validation as a potential target for treating acute and chronic pain. While several different chemotypes have been advanced as selective inhibitors, a quinoxaline carboxamide core structure was identified as a particularly attractive core structure due to very high sodium channel subtype selectivity. However, poor solubility and overall ADME properties need to be improved. Scaffold hopping to a central trifluoromethyl pyridine followed by optimization of distal substituents resulted in improved overall properties. Several advanced lead compounds have been identified with excellent potency, selectivity, solubility, and pharmacokinetics. Preliminary mechanism of action studies suggest that this class of compounds are voltage and state independent inhibitors that bind to a novel site on the Na_v1.8 channel.