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<sub>V</sub>1.7
Inhibitors for the Treatment of Pain
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Abstract
The
sodium channel Na<sub>V</sub>1.7 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<sub>V</sub>1.7, with high selectivity over the cardiac isoform Na<sub>V</sub>1.5. 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<sub>V</sub>1.7 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<sub>V</sub>1.7 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