Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na_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 <i>N</i>-([1,2,4]­triazolo­[4,3-<i>a</i>]­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 <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance in mouse, rat, and dog. Compound <b>13</b> also displayed excellent efficacy in a transgenic mouse model of induced pain.