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ID: ALA1140726

Journal: J Med Chem

Title: 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.

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

Abstract: 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.

CiteXplore: 18176998

DOI: 10.1021/jm070637u