Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N‑([1,2,4]Triazolo[4,3‑a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNa_V1.7 Inhibitors for the Treatment of Pain

The sodium channel Na_V1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na_V1.7, with high selectivity over the cardiac isoform Na_V1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]­triazolo­[4,3-a]­pyridin-3-yl)­methanesulfonamides as selective Na_V1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of Na_V1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.