Bioorganic & medicinal chemistry letters · 2012
A novel series of pyrazolylpiperidine N-type calcium channel blockers.
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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
Аннотация
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.