Structural hybridization of pyrrolidine-based T-type calcium channel inhibitors and exploration of their analgesic effects in a neuropathic pain model

Bioorg Med Chem Lett. 2019 May 15;29(10):1168-1172. doi: 10.1016/j.bmcl.2019.03.026. Epub 2019 Mar 21.

Abstract

Highly effective and safe drugs for the treatment of neuropathic pain are urgently required and it was shown that blocking T-type calcium channels can be a promising strategy for drug development for neuropathic pain. We have developed pyrrolidine-based T-type calcium channel inhibitors by structural hybridization and subsequent assessment of in vitro activities against Cav3.1 and Cav3.2 channels. Profiling of in vitro ADME properties of compounds was also carried out. The representative compound 17h showed comparable in vivo efficacy to gabapentin in the SNL model, which indicates T-type calcium channel inhibitors can be developed as effective therapeutics for neuropathic pain.

Keywords: Neuropathic pain; Pyrrolidine; Spinal nerve ligation; T-type calcium channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemistry*
  • Analgesics / pharmacology
  • Animals
  • Calcium Channel Blockers / chemistry*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, T-Type / metabolism*
  • Calcium Signaling / drug effects
  • Disease Models, Animal
  • Gabapentin / metabolism
  • Ganglia, Spinal / drug effects
  • Humans
  • Ligation
  • Microsomes, Liver / drug effects
  • Molecular Structure
  • Neuralgia / drug therapy*
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • Pyrrolidines
  • Gabapentin