1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of Na V 1.7 inhibition.

Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit NaV 1.7 and demonstrate high levels of selectivity over other NaV isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective NaV 1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over NaV 1.5 and favorable pharmacokinetics in rodents.