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.
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Authors | Marc 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 |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 18
Issue 22
Pg. 7816-25
(Nov 15 2010)
ISSN: 1464-3391 [Electronic] England |
PMID | 20965738
(Publication Type: Journal Article)
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Copyright | Copyright © 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
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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
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