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.
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Authors | Nalin 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 |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 22
Issue 12
Pg. 4080-3
(Jun 15 2012)
ISSN: 1464-3405 [Electronic] England |
PMID | 22608964
(Publication Type: Journal Article)
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Copyright | Copyright © 2012 Elsevier Ltd. All rights reserved. |
Chemical References |
- Analgesics
- Calcium Channel Blockers
- Calcium Channels, N-Type
- Piperidines
- Pyrazoles
- omega-Conotoxins
- ziconotide
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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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