Identification of a potent, state-dependent inhibitor of Nav1. 7 with oral efficacy in the formalin model of persistent pain

…, B Du, E Feric, M Hierl, L Huang, D Immke…

Index: Bregman, Howard; Berry, Loren; Buchanan, John L.; Chen, April; Du, Bingfan; Feric, Elma; Hierl, Markus; Huang, Liyue; Immke, David; Janosky, Brett; Johnson, Danielle; Li, Xingwen; Ligutti, Joseph; Liu, Dong; Malmberg, Annika; Matson, David; McDermott, Jeff; Miu, Peter; Nguyen, Hanh Nho; Patel, Vinod F.; Waldon, Daniel; Wilenkin, Ben; Zheng, Xiao Mei; Zou, Anruo; McDonough, Stefan I.; Dimauro, Erin F. Journal of Medicinal Chemistry, 2011 , vol. 54, # 13 p. 4427 - 4445

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Citation Number: 34

Abstract

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–activity 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 ...