title: The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Na(v)1.7.
abstract: The voltage gated sodium channel Nav1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Nav1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Nav1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Nav1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Nav1.7 inhibitor with a thousand-fold selectivity over Nav1.5 and negligible CYP inhibition.
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada. Electronic address: ssun@xenon-pharma.com.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Sun
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Alla Y
authors.initials: AY
authors.lastname: Zenova
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Chafeev
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Zaihui
authors.initials: Z
authors.lastname: Zhang
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: Rainbow
authors.initials: R
authors.lastname: Kwan
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Mike 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: Clint
authors.initials: C
authors.lastname: Young
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: Renata M
authors.initials: RM
authors.lastname: Oballa
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D051544:Cytochrome P-450 CYP3A; D004791:Enzyme Inhibitors; D062556:NAV1.7 Voltage-Gated Sodium Channel; D013449:Sulfonamides; D061567:Voltage-Gated Sodium Channel Blockers; D000096926:Benzenesulfonamides; C510163:CYP3A4 protein, human
keywords: Benzenesulfonamide; Na(v)1.7; Pain; Sodium channel