Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1055-60. doi: 10.1016/j.bmcl.2011.11.111. Epub 2011 Dec 6.


Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • NAV1.7 Voltage-Gated Sodium Channel
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Rats
  • Sodium Channels / metabolism*
  • Structure-Activity Relationship


  • Ligands
  • NAV1.7 Voltage-Gated Sodium Channel
  • Pyrimidinones
  • SCN9A protein, human
  • Sodium Channels