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Discovery of Indole- and Indazole-acylsulfonamides as Potent and Selective NaV1.7 Inhibitors for the Treatment of Pain

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posted on 21.12.2018, 00:00 by Guanglin Luo, Ling Chen, Amy Easton, Amy Newton, Clotilde Bourin, Eric Shields, Kathy Mosure, Matthew G. Soars, Ronald J. Knox, Michele Matchett, Rick L. Pieschl, Debra J. Post-Munson, Shuya Wang, James Herrington, John Graef, Kimberly Newberry, Digavalli V. Sivarao, Arun Senapati, Linda J. Bristow, Nicholas A. Meanwell, Lorin A. Thompson, Carolyn Dzierba
3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund’s adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.