Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain

  • Bioorg Med Chem. 2008 Jun 15;16(12):6379-86. doi: 10.1016/j.bmc.2008.05.003.
Irene Drizin  1 ,  Robert J Gregg ,  Marc J C Scanio ,  Lei Shi ,  Michael F Gross ,  Robert N Atkinson ,  James B Thomas ,  Matthew S Johnson ,  William A Carroll ,  Brian E Marron ,  Mark L Chapman ,  Dong Liu ,  Michael J Krambis ,  Char-Chang Shieh ,  XuFeng Zhang ,  Gricelda Hernandez ,  Donna M Gauvin ,  Joseph P Mikusa ,  Chang Z Zhu ,  Shailen Joshi ,  Prisca Honore ,  Kennan C Marsh ,  Rosemarie Roeloffs ,  Stephen Werness ,  Douglas S Krafte ,  Michael F Jarvis ,  Connie R Faltynek ,  Michael E Kort
Affiliations
  • 1. Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. [email protected]
PMID: 18501613 DOI: 10.1016/j.bmc.2008.05.003
Abstract

The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated Sodium Channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant Sodium Channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used Sodium Channel blockers mexiletine and lamotrigine.