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
Keywords : Administration,Oral,Animals,chemistry,cytology,Disease Models,Animal,Drug Evaluation,Preclinical,drug therapy,Ganglia,Spinal,Humans,metabolism,Microsomes,NAV1.8 Voltage-Gated Sodium Channel,Neuralgia,Neurons,Pain,pharmacokinetics,Pyrazines,Rats,Sodium Channel Blockers,Sodium Channels,Structure-Activity Relationship,therapeutic use,United States,, Biological,Evaluation,Potent, hospital of st john and st elizabeth consultants
Date of Publication : 2010 Nov 15
Authors : Scanio MJ;Shi L;Drizin I;Gregg RJ;Atkinson RN;Thomas JB;Johnson MS;Chapman ML;Liu D;Krambis MJ;Liu Y;Shieh CC;Zhang X;Simler GH;Joshi S;Honore P;Marsh KC;Knox A;Werness S;Antonio B;Krafte DS;Jarvis MF;Faltynek CR;Marron BE;Kort ME;
Organisation : Global Pharmaceutical Research and Development, Abbott Laboratories, Dept R4PM, Bldg. AP9A, 100 Abbott Park Road, Abbott Park, IL 60064-6117, United States. marc.scanio@abbott.com
Journal of Publication : Bioorg Med Chem
Pubmed Link : https://www.ncbi.nlm.nih.gov/pubmed/20965738
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