title: Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models.
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.
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Thilo
authors.initials: T
authors.lastname: Focken
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Navjot
authors.initials: N
authors.lastname: Chahal
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Maxim
authors.initials: M
authors.lastname: Dauphinais
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Grimwood
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Sultan
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Hemeon
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Bichler
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Bogucki
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Waldbrook
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Girish
authors.initials: G
authors.lastname: Bankar
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Sojo
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Clint
authors.initials: C
authors.lastname: Young
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Sophia
authors.initials: S
authors.lastname: Lin
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Noah
authors.initials: N
authors.lastname: Shuart
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Rainbow
authors.initials: R
authors.lastname: Kwan
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jae H
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Safina
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Johnson
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Dehnhardt
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Renata M
authors.initials: RM
authors.lastname: Oballa
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Cohen
authors.affiliation: Xenon Pharmaceuticals, Inc. , 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: C Lee
authors.initials: CL
authors.lastname: Robinette
keywords: NaV1.5; NaV1.7; Sodium channel; aryl sulfonamide; cold allodynia; formalin model; pain