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
  • 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.
Products