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

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

  • ACS Med Chem Lett. 2016 Jan 19;7(3):277-82. doi: 10.1021/acsmedchemlett.5b00447.
Thilo Focken 1,  Shifeng Liu 1,  Navjot Chahal 1,  Maxim Dauphinais 1,  Michael E Grimwood 1,  Sultan Chowdhury 1,  Ivan Hemeon 1,  Paul Bichler 1,  David Bogucki 1,  Matthew Waldbrook 1,  Girish Bankar 1,  Luis E Sojo 1,  Clint Young 1,  Sophia Lin 1,  Noah Shuart 1,  Rainbow Kwan 1,  Jodie Pang 2,  Jae H Chang 2,  Brian S Safina 2,  Daniel P Sutherlin 2,  J P Johnson Jr 1,  Christoph M Dehnhardt 1,  Tarek S Mansour 1,  Renata M Oballa 1,  Charles J Cohen 1,  C Lee Robinette 1
Affiliations

Affiliations

  • 1 Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
  • 2 Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 26985315 DOI: 10.1021/acsmedchemlett.5b00447
Abstract

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.

Keywords

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

Figures
Products