Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Na(v)1.8 sodium channel with efficacy in a model of neuropathic pain.
Na(v)1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Na(v)1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Na(v)1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Na(v)1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration.
Global Pharmaceutical Research and Development, Abbott Laboratories, Dept R4PM, Bldg. AP9A, 100 Abbott Park Road, Abbott Park, IL 60064-6117, United States. marc.scanio@abbott.com
Marc J C
MJ
Scanio
Lei
L
Shi
Irene
I
Drizin
Robert J
RJ
Gregg
Robert N
RN
Atkinson
James B
JB
Thomas
Matthew S
MS
Johnson
Mark L
ML
Chapman
Dong
D
Liu
Michael J
MJ
Krambis
Yi
Y
Liu
Char-Chang
CC
Shieh
Xufeng
X
Zhang
Gricelda H
GH
Simler
Shailen
S
Joshi
Prisca
P
Honore
Kennan C
KC
Marsh
Alison
A
Knox
Stephen
S
Werness
Brett
B
Antonio
Douglas S
DS
Krafte
Michael F
MF
Jarvis
Connie R
CR
Faltynek
Brian E
BE
Marron
Michael E
ME
Kort
D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009437:Neuralgia / Q000188:drug therapy*; D009474:Neurons / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D062559:NAV1.8 Voltage-Gated Sodium Channel; D011719:Pyrazines; C568317:SCN10A protein, human; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels