N -Aryl Indoles as a Novel Class of Potent Na V 1.7 Inhibitors

A novel class of potent Na V 1.7 inhibitors has been discovered. The replacement of diaryl ether in compound I was investigated to enhance mouse Na V 1.7 inhibitory activity, which resulted in the discovery of N -aryl indoles. The introduction of the 3-methyl group is crucial for high Na V 1.7 in vitro potency. The adjustment of lipophilicity led to the discovery of 2e . Compound 2e (DS43260857) demonstrated high in vitro potencies against both human and mouse Na V 1.7 with high selectivity over Na V 1.1, Na V 1.5, and hERG. In vivo evaluations revealed 2e demonstrating potent efficacy in PSL mice with excellent pharmacokinetics.