Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain.
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.
Drizin
Irene
I
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. irene.drizin@abbott.com
Gregg
Robert J
RJ
Scanio
Marc J C
MJ
Shi
Lei
L
Gross
Michael F
MF
Atkinson
Robert N
RN
Thomas
James B
JB
Johnson
Matthew S
MS
Carroll
William A
WA
Marron
Brian E
BE
Chapman
Mark L
ML
Liu
Dong
D
Krambis
Michael J
MJ
Shieh
Char-Chang
CC
Zhang
XuFeng
X
Hernandez
Gricelda
G
Gauvin
Donna M
DM
Mikusa
Joseph P
JP
Zhu
Chang Z
CZ
Joshi
Shailen
S
Honore
Prisca
P
Marsh
Kennan C
KC
Roeloffs
Rosemarie
R
Werness
Stephen
S
Krafte
Douglas S
DS
Jarvis
Michael F
MF
Faltynek
Connie R
CR
Kort
Michael E
ME
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
D018712:Analgesics, Non-Narcotic; D051638:Ether-A-Go-Go Potassium Channels; D005663:Furans; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels