Discovery of pyrrolo-benzo-1,4-diazines as potent Na(v)1.7 sodium channel blockers

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4110-3. doi: 10.1016/j.bmcl.2014.07.060. Epub 2014 Jul 29.

Abstract

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.

Keywords: Nav1.5; Nav1.7; Pain; Pyrrolo-benzo-1,4-diazine; Sodium channel blockers.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • NAV1.7 Voltage-Gated Sodium Channel / metabolism*
  • Quinoxalines / chemical synthesis
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology*
  • Sodium Channel Blockers / chemical synthesis
  • Sodium Channel Blockers / chemistry
  • Sodium Channel Blockers / pharmacology*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • NAV1.7 Voltage-Gated Sodium Channel
  • Quinoxalines
  • Sodium Channel Blockers
  • Spiro Compounds