Bioavailable pyrrolo-benzo-1,4-diazines as Na(v)1.7 sodium channel blockers for the treatment of pain

Bioorg Med Chem Lett. 2014 Nov 1;24(21):4958-62. doi: 10.1016/j.bmcl.2014.09.038. Epub 2014 Sep 19.

Abstract

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 μM.

Keywords: Na(v)1.5; Na(v)1.7; Pain; Sodium channel.

MeSH terms

  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Ganglia, Spinal / drug effects*
  • Molecular Structure
  • NAV1.7 Voltage-Gated Sodium Channel / chemistry*
  • Neuralgia / drug therapy*
  • Patch-Clamp Techniques
  • Quinoxalines / chemistry
  • Rats
  • Sodium Channel Blockers / chemistry
  • Sodium Channel Blockers / pharmacology*
  • Spinal Nerves / drug effects*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

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