A novel series of pyrazolylpiperidine N-type calcium channel blockers |
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Authors: | Subasinghe Nalin L Wall Mark J Winters Michael P Qin Ning Lubin Mary Lou Finley Michael F A Brandt Michael R Neeper Michael P Schneider Craig R Colburn Raymond W Flores Christopher M Sui Zhihua |
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Institution: | Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. NSUBASIN@its.jnj.com |
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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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