1. Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Nav1.8 sodium channel with efficacy in a model of neuropathic pain
- Author
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Brett Antonio, Robert J. Gregg, Gricelda H. Simler, Matthew S Johnson, Yi Liu, Dong Liu, Marc J. C. Scanio, Prisca Honore, Alison Knox, James B. Thomas, Shailen K. Joshi, Mark L. Chapman, Brian E. Marron, Irene Drizin, Douglas S. Krafte, Connie R. Faltynek, Robert N. Atkinson, Xu-Feng Zhang, Michael J. Krambis, Kort Michael E, Michael F. Jarvis, Stephen Werness, Kennan C. Marsh, Lei Shi, and Char-Chang Shieh
- Subjects
Clinical Biochemistry ,Analgesic ,Drug Evaluation, Preclinical ,Administration, Oral ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Sodium Channels ,NAV1.8 Voltage-Gated Sodium Channel ,Structure-Activity Relationship ,Sodium channel blocker ,Oral administration ,In vivo ,Ganglia, Spinal ,Microsomes ,Drug Discovery ,Animals ,Humans ,Molecular Biology ,Neurons ,Chemistry ,Sodium channel ,Organic Chemistry ,Rats ,Blockade ,Disease Models, Animal ,Nociception ,Pyrazines ,Neuropathic pain ,Neuralgia ,Molecular Medicine ,Sodium Channel Blockers - 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.
- Published
- 2010
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