The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Na(v)1.7

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4397-4401. doi: 10.1016/j.bmcl.2014.08.017. Epub 2014 Aug 14.

Abstract

The voltage gated sodium channel Nav1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Nav1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Nav1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Nav1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Nav1.7 inhibitor with a thousand-fold selectivity over Nav1.5 and negligible CYP inhibition.

Keywords: Benzenesulfonamide; Na(v)1.7; Pain; Sodium channel.

MeSH terms

  • Cytochrome P-450 CYP3A / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • NAV1.7 Voltage-Gated Sodium Channel / metabolism*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Voltage-Gated Sodium Channel Blockers / chemical synthesis
  • Voltage-Gated Sodium Channel Blockers / chemistry
  • Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

  • Enzyme Inhibitors
  • NAV1.7 Voltage-Gated Sodium Channel
  • Sulfonamides
  • Voltage-Gated Sodium Channel Blockers
  • benzenesulfonamide
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human