Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3676-81. doi: 10.1016/j.bmcl.2011.04.088. Epub 2011 Apr 24.

Abstract

Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na(V)1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts.

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Molecular Structure
  • NAV1.7 Voltage-Gated Sodium Channel
  • Oxindoles
  • Pain*
  • Sodium Channels / metabolism*
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Indoles
  • NAV1.7 Voltage-Gated Sodium Channel
  • Oxindoles
  • SCN9A protein, human
  • Sodium Channels
  • Spiro Compounds
  • XEN 907
  • 2-oxindole