Bioorganic & Medicinal Chemistry Letters 2012-06-15

A novel series of pyrazolylpiperidine N-type calcium channel blockers

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

Index: Bioorg. Med. Chem. Lett. 22(12) , 4080-3, (2012)

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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.Copyright © 2012 Elsevier Ltd. All rights reserved.