Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain

. The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na v1.8 (PN3) as well as the Na v1.2 and Na v1.5 subtypes. Benchmark c...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-06, Vol.16 (12), p.6379-6386
Main Authors: Drizin, Irene, Gregg, Robert J., Scanio, Marc J.C., Shi, Lei, Gross, Michael F., Atkinson, Robert N., Thomas, James B., Johnson, Matthew S., Carroll, William A., Marron, Brian E., Chapman, Mark L., Liu, Dong, Krambis, Michael J., Shieh, Char-Chang, Zhang, XuFeng, Hernandez, Gricelda, Gauvin, Donna M., Mikusa, Joseph P., Zhu, Chang Z., Joshi, Shailen, Honore, Prisca, Marsh, Kennan C., Roeloffs, Rosemarie, Werness, Stephen, Krafte, Douglas S., Jarvis, Michael F., Faltynek, Connie R., Kort, Michael E.
Format: Article
Language:English
Subjects:
Analgesics
Analgesics, Non-Narcotic - chemical synthesis
Analgesics, Non-Narcotic - chemistry
Analgesics, Non-Narcotic - pharmacology
Animals
Biological and medical sciences
Blocker
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
Furan piperazine
Furans - chemical synthesis
Furans - chemistry
Furans - pharmacology
Humans
Male
Medical sciences
Mice
Nav1.8
Neuralgia - drug therapy
Neuropharmacology
Pain
Pharmacology. Drug treatments
Piperazines - chemical synthesis
Piperazines - chemistry
Piperazines - pharmacology
PN3
Rats
Rats, Sprague-Dawley
Sodium Channel Blockers - chemical synthesis
Sodium Channel Blockers - chemistry
Sodium Channel Blockers - pharmacology
Sodium channels
Sodium Channels - drug effects
Structure-Activity Relationship
Voltage-gated
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Summary:. The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na v1.8 (PN3) as well as the Na v1.2 and Na v1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.05.003