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ACS Med Chem Lett. 2016 Jan 19;7(3):277-82. doi: 10.1021/acsmedchemlett.5b00447. eCollection 2016 Mar 10.

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models.

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Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.


We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain.


NaV1.5; NaV1.7; Sodium channel; aryl sulfonamide; cold allodynia; formalin model; pain

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