Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors

Bioorg Med Chem Lett. 2012 Jun 15;22(12):4153-8. doi: 10.1016/j.bmcl.2012.04.054. Epub 2012 Apr 19.

Abstract

We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (~120-fold) and L-type (~3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology
  • Animals
  • Calcium Channel Blockers / chemical synthesis*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / metabolism
  • Calcium Channels, N-Type / metabolism*
  • Disease Models, Animal
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / metabolism
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Nerves / drug effects*
  • Spinal Nerves / metabolism
  • Structure-Activity Relationship

Substances

  • 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine
  • Analgesics
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Calcium Channels, N-Type
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Piperazines