A novel series of pyrazolylpiperidine N-type calcium channel blockers
| Autor: | Michael R. Brandt, Michael F.A. Finley, Ning Qin, Michael P. Winters, Craig R. Schneider, Mary Lou Lubin, Michael P. Neeper, Nalin L. Subasinghe, Zhihua Sui, Raymond W. Colburn, Christopher M. Flores, Wall Mark |
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| Rok vydání: | 2012 |
| Předmět: |
Patch-Clamp Techniques
Clinical Biochemistry Pharmaceutical Science Pharmacology N-type calcium channel Biochemistry omega-Conotoxins Cell Line Structure-Activity Relationship Calcium Channels N-Type Piperidines In vivo Drug Discovery medicine Animals Humans Potency Molecular Biology Analgesics Ziconotide Chemistry Calcium channel Organic Chemistry Chronic pain Metabolic stability Calcium Channel Blockers medicine.disease High-Throughput Screening Assays Rats Neuropathic pain Neuralgia Pyrazoles Molecular Medicine Chronic Pain medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:4080-4083 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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