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

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

  • J Med Chem. 2011 Jul 14;54(13):4427-45. doi: 10.1021/jm200018k.
Howard Bregman 1,  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
Affiliations

Affiliation

  • 1 Department of Chemistry Research and Discovery, Amgen Inc., Cambridge, Massachusetts 02142, United States. hbregman@amgen.com
PMID: 21634377 DOI: 10.1021/jm200018k
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 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.

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