title: Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain.
abstract: Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6100, USA. michael.e.kort@abbott.com
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gregg
authors.forename: Marc J C
authors.initials: MJ
authors.lastname: Scanio
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gross
authors.forename: Robert N
authors.initials: RN
authors.lastname: Atkinson
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Johnson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Pacofsky
authors.forename: James B
authors.initials: JB
authors.lastname: Thomas
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krambis
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Char-Chang
authors.initials: CC
authors.lastname: Shieh
authors.forename: Xufeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Gricelda
authors.initials: G
authors.lastname: Hernandez
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Shailen
authors.initials: S
authors.lastname: Joshi
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Roeloffs
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Murray
authors.forename: Jinrong
authors.initials: J
authors.lastname: Liu
authors.forename: Stephen
authors.initials: S
authors.lastname: Werness
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Krafte
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chapman
authors.forename: Brian E
authors.initials: BE
authors.lastname: Marron
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D018408:Patch-Clamp Techniques; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: C528494:5-(4-chlorophenyl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide; C528493:5-(4-cyanophenyl)-N-(3-methylphenyl)furan-2-carboxamide; D000577:Amides; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005663:Furans; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels