Subtype-selective Na(v)1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives

  • Bioorg Med Chem Lett. 2010 Nov 15;20(22):6812-5. doi: 10.1016/j.bmcl.2010.08.121.
Michael E Kort  1 ,  Robert N Atkinson ,  James B Thomas ,  Irene Drizin ,  Matthew S Johnson ,  Matthew A Secrest ,  Robert J Gregg ,  Marc J C Scanio ,  Lei Shi ,  Ahmed H Hakeem ,  Mark A Matulenko ,  Mark L Chapman ,  Michael J Krambis ,  Dong Liu ,  Char-Chang Shieh ,  XuFeng Zhang ,  Gricelda Simler ,  Joseph P Mikusa ,  Chengmin Zhong ,  Shailen Joshi ,  Prisca Honore ,  Rosemarie Roeloffs ,  Stephen Werness ,  Brett Antonio ,  Kennan C Marsh ,  Connie R Faltynek ,  Douglas S Krafte ,  Michael F Jarvis ,  Brian E Marron
Affiliations
  • 1. Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA. [email protected]
PMID: 20855211 DOI: 10.1016/j.bmcl.2010.08.121
Abstract

A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 Sodium Channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic Pain.

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