Discovery and optimization of a novel series of pyrazolyltetrahydropyran N-type calcium channel (Cav 2.2) blockers for the treatment of pain

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3780-3783. doi: 10.1016/j.bmcl.2018.10.007. Epub 2018 Oct 12.

Abstract

A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.

Keywords: CCI model; CFA model; Cav 2.2; N-type calcium channel; Pain; Pyrazoles.

MeSH terms

  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Calcium / metabolism
  • Calcium Channel Blockers / chemistry*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channel Blockers / therapeutic use*
  • Calcium Channels, N-Type / metabolism*
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Patch-Clamp Techniques
  • Pyrans / chemistry
  • Pyrans / pharmacology
  • Pyrans / therapeutic use
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Analgesics
  • Cacna1b protein, rat
  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Pyrans
  • Pyrazoles
  • Calcium