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A novel series of pyrazolylpiperidine N-type calcium channel blockers.

Abstract
Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.
AuthorsNalin L Subasinghe, Mark J Wall, Michael P Winters, Ning Qin, Mary Lou Lubin, Michael F A Finley, Michael R Brandt, Michael P Neeper, Craig R Schneider, Raymond W Colburn, Christopher M Flores, Zhihua Sui
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 12 Pg. 4080-3 (Jun 15 2012) ISSN: 1464-3405 [Electronic] England
PMID22608964 (Publication Type: Journal Article)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Analgesics
  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Piperidines
  • Pyrazoles
  • omega-Conotoxins
  • ziconotide
Topics
  • Analgesics (chemical synthesis, therapeutic use)
  • Animals
  • Calcium Channel Blockers (chemical synthesis, therapeutic use)
  • Calcium Channels, N-Type (metabolism)
  • Cell Line
  • Chronic Pain (drug therapy, metabolism)
  • High-Throughput Screening Assays
  • Humans
  • Neuralgia (drug therapy, metabolism)
  • Patch-Clamp Techniques
  • Piperidines (chemical synthesis, therapeutic use)
  • Pyrazoles (chemical synthesis, therapeutic use)
  • Rats
  • Structure-Activity Relationship
  • omega-Conotoxins (therapeutic use)

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