PT  - JOURNAL ARTICLE
AU  - Thomas J Kornecook
AU  - Ruoyuan Yin
AU  - Stephen Altmann
AU  - Xuhai Be
AU  - Virginia Berry
AU  - Christopher P Ilch
AU  - Michael Jarosh
AU  - Danielle Johnson
AU  - Josie H Lee
AU  - Sonya G Lehto
AU  - Joseph Ligutti
AU  - Dong Liu
AU  - Jason Luther
AU  - David Matson
AU  - Danny Ortuno
AU  - John Roberts
AU  - Kristin Taborn
AU  - Jinti Wang
AU  - Matthew M Weiss
AU  - Violeta Yu
AU  - Dawn X. D. Zhu
AU  - Robert T Fremeau
AU  - Bryan D Moyer
TI  - Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel Na<sub>V</sub>1.7
AID  - 10.1124/jpet.116.239590
DP  - 2017 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.116.239590
4099  - http://jpet.aspetjournals.org/content/early/2017/05/04/jpet.116.239590.short
4100  - http://jpet.aspetjournals.org/content/early/2017/05/04/jpet.116.239590.full
AB  - Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglia (DRG) neurons with an IC50 of 3.1 nM in whole cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state. AMG8379 was 100 to 1000-fold selective over other NaV family members, including NaV1.4 expressed in muscle and NaV1.5 expressed in heart, as well as TTX-resistant NaV channels in DRG neurons. Using an ex vivo mouse skin-nerve preparation, AMG8379 blocked mechanically-induced action potential firing in C-fibers in both a time-dependent and dose-dependent manner. AMG8379 similarly reduced the frequency of thermally-induced C-fiber spiking, whereas AMG8380 affected neither mechanical nor thermal responses. In vivo target engagement of AMG8379 in mice was evaluated in multiple NaV1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels. AMG8379 is a potent and selective NaV1.7 inhibitor that blocks sodium current in heterologous cells as well as DRG neurons, inhibits action potential firing in peripheral nerve fibers, and exhibits pharmacodynamic effects in translatable models of both itch and pain.