Identification of a Potent, State-Dependent Inhibitor of Nav1.7 with Oral Efficacy in the Formalin Model of Persistent Pain

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• 作者：Howard Bregman ; Loren Berry ; John L. Buchanan ; April Chen ; Bingfan Du ; Elma Feric ; Markus Hierl ; Liyue Huang ; David Immke ; Brett Janosky ; Danielle Johnson ; Xingwen Li ; Joseph Ligutti ; Dong Liu ; Annika Malmberg ; David Matson ; Jeff McDermott ; Peter Miu ; Hanh Nho Nguyen ; Vinod F. Patel ; Daniel Waldon ; Ben Wilenkin ; Xiao Mei Zheng ; Anruo Zou ; Stefan I. McDonough ; Erin F. DiMauro
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4427-4445
• 全文大小：1256K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure鈥揳ctivity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.