Subtype-selective Na(v)1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives.
A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
Kort
Michael E
ME
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA. michael.e.kort@abbott.com
Atkinson
Robert N
RN
Thomas
James B
JB
Drizin
Irene
I
Johnson
Matthew S
MS
Secrest
Matthew A
MA
Gregg
Robert J
RJ
Scanio
Marc J C
MJ
Shi
Lei
L
Hakeem
Ahmed H
AH
Matulenko
Mark A
MA
Chapman
Mark L
ML
Krambis
Michael J
MJ
Liu
Dong
D
Shieh
Char-Chang
CC
Zhang
XuFeng
X
Simler
Gricelda
G
Mikusa
Joseph P
JP
Zhong
Chengmin
C
Joshi
Shailen
S
Honore
Prisca
P
Roeloffs
Rosemarie
R
Werness
Stephen
S
Antonio
Brett
B
Marsh
Kennan C
KC
Faltynek
Connie R
CR
Krafte
Douglas S
DS
Jarvis
Michael F
MF
Marron
Brian E
BE
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D009536:Niacinamide / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D026941:Sodium Channel Blockers; D009536:Niacinamide