title: Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain.
abstract: The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. irene.drizin@abbott.com
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: James B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Johnson
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
authors.forename: Brian E
authors.initials: BE
authors.lastname: Marron
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chapman
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krambis
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: Donna M
authors.initials: DM
authors.lastname: Gauvin
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Shailen
authors.initials: S
authors.lastname: Joshi
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Roeloffs
authors.forename: Stephen
authors.initials: S
authors.lastname: Werness
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Krafte
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D018712:Analgesics, Non-Narcotic; D051638:Ether-A-Go-Go Potassium Channels; D005663:Furans; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels