|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
3
|
|
pubmed:dateCreated |
2008-2-8
|
|
pubmed:abstractText |
Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Feb
|
|
pubmed:issn |
0022-2623
|
|
pubmed:author |
pubmed-author:AtkinsonRobert NRN,
pubmed-author:CarrollWilliam AWA,
pubmed-author:ChapmanMark LML,
pubmed-author:DrizinIreneI,
pubmed-author:FaltynekConnie RCR,
pubmed-author:GreggRobert JRJ,
pubmed-author:GrothMichael JMJ,
pubmed-author:HernandezGriceldaG,
pubmed-author:HonorePriscaP,
pubmed-author:JarvisMichael FMF,
pubmed-author:JohnsonMatthew SMS,
pubmed-author:JoshiShailenS,
pubmed-author:KortMichael EME,
pubmed-author:KrafteDouglas SDS,
pubmed-author:KrambisMichael JMJ,
pubmed-author:LiuDongD,
pubmed-author:LiuJinrongJ,
pubmed-author:MarronBrian EBE,
pubmed-author:MarshKennan CKC,
pubmed-author:MikusaJoseph PJP,
pubmed-author:MurrayBernard PBP,
pubmed-author:PacofskyGregory JGJ,
pubmed-author:RoeloffsRosemarieR,
pubmed-author:ScanioMarc J CMJ,
pubmed-author:ShiLeiL,
pubmed-author:ShiehChar-ChangCC,
pubmed-author:ThomasJames BJB,
pubmed-author:WernessStephenS,
pubmed-author:ZhangXufengX,
pubmed-author:ZhongChengminC
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
14
|
|
pubmed:volume |
51
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
407-16
|
|
pubmed:dateRevised |
2010-8-16
|
|
pubmed:meshHeading |
pubmed-meshheading:18176998-Amides,
pubmed-meshheading:18176998-Analgesics,
pubmed-meshheading:18176998-Animals,
pubmed-meshheading:18176998-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:18176998-Cell Line,
pubmed-meshheading:18176998-Cricetinae,
pubmed-meshheading:18176998-Cricetulus,
pubmed-meshheading:18176998-Furans,
pubmed-meshheading:18176998-Ganglia, Spinal,
pubmed-meshheading:18176998-Humans,
pubmed-meshheading:18176998-Male,
pubmed-meshheading:18176998-Mice,
pubmed-meshheading:18176998-Nerve Tissue Proteins,
pubmed-meshheading:18176998-Neurons,
pubmed-meshheading:18176998-Pain,
pubmed-meshheading:18176998-Patch-Clamp Techniques,
pubmed-meshheading:18176998-Peripheral Nervous System Diseases,
pubmed-meshheading:18176998-Rats,
pubmed-meshheading:18176998-Rats, Sprague-Dawley,
pubmed-meshheading:18176998-Recombinant Proteins,
pubmed-meshheading:18176998-Sodium Channel Blockers,
pubmed-meshheading:18176998-Sodium Channels,
pubmed-meshheading:18176998-Structure-Activity Relationship
|
|
pubmed:year |
2008
|
|
pubmed:articleTitle |
Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain.
|
|
pubmed:affiliation |
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6100, USA. michael.e.kort@abbott.com
|
|
pubmed:publicationType |
Journal Article,
In Vitro
|
