HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.

Abstract
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.
AuthorsMarc J C Scanio, Lei Shi, Irene Drizin, Robert J Gregg, Robert N Atkinson, James B Thomas, Matthew S Johnson, Mark L Chapman, Dong Liu, Michael J Krambis, Yi Liu, Char-Chang Shieh, Xufeng Zhang, Gricelda H Simler, Shailen Joshi, Prisca Honore, Kennan C Marsh, Alison Knox, Stephen Werness, Brett Antonio, Douglas S Krafte, Michael F Jarvis, Connie R Faltynek, Brian E Marron, Michael E Kort
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 22 Pg. 7816-25 (Nov 15 2010) ISSN: 1464-3391 [Electronic] England
PMID20965738 (Publication Type: Journal Article)
CopyrightCopyright © 2010. Published by Elsevier Ltd.
Chemical References
  • NAV1.8 Voltage-Gated Sodium Channel
  • Pyrazines
  • SCN10A protein, human
  • Scn10a protein, rat
  • Sodium Channel Blockers
  • Sodium Channels
Topics
  • Administration, Oral
  • Animals
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Ganglia, Spinal (cytology)
  • Humans
  • Microsomes (metabolism)
  • NAV1.8 Voltage-Gated Sodium Channel
  • Neuralgia (drug therapy)
  • Neurons (metabolism)
  • Pyrazines (chemistry, pharmacokinetics, therapeutic use)
  • Rats
  • Sodium Channel Blockers (chemistry, pharmacokinetics, therapeutic use)
  • Sodium Channels (chemistry, metabolism)
  • Structure-Activity Relationship

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: