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.

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. Research Abstract Details 

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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. Abstract Text:

Michael E Kort,Irene Drizin,Robert J Gregg,Marc J C Scanio,Lei Shi,Michael F Gross,Robert N Atkinson,Matthew S Johnson,Gregory J Pacofsky,James B Thomas,William A Carroll,Michael J Krambis,Dong Liu,Char-Chang Shieh,Xufeng Zhang,Gricelda Hernandez,Joseph P Mikusa,Chengmin Zhong,Shailen Joshi,Prisca Honore,Rosemarie Roeloffs,Kennan C Marsh,Bernard P Murray,Jinrong Liu,Stephen Werness,Connie R Faltynek,Douglas S Krafte,Michael F Jarvis,Mark L Chapman,Brian E Marron,

Na v1.8 (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 Na v1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Na v1.8 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 (IC 50 < 10 nM) of the human Na v1.8 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 (Na v1.2, Na v1.5, Na v1.7) 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.

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. Publishing Authors By Initials

ME Kort,I Drizin,RJ Gregg,MJ Scanio,L Shi,MF Gross,RN Atkinson,MS Johnson,GJ Pacofsky,JB Thomas,WA Carroll,MJ Krambis,D Liu,CC Shieh,X Zhang,G Hernandez,JP Mikusa,C Zhong,S Joshi,P Honore,R Roeloffs,KC Marsh,BP Murray,J Liu,S Werness,CR Faltynek,DS Krafte,MF Jarvis,ML Chapman,BE Marron,

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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. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Journal of medicinal chemistry

VOLUME: 51

Page Numbers: 407-16

Journal Abbreviation: J. Med. Chem.

ISSN: 0022-2623

DAY: 5

MONTH: 01

YEAR: 2008

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. Information

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LANGUAGE: eng

NlmUniqueID: 9716531

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AFFILIATION: michael.e.kort@abbott.com.

Country: United States

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MEDLINETA: J Med Chem

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