A novel series of pyrazolylpiperidine N-type calcium channel blockers.

Autor: Subasinghe NL; Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. NSUBASIN@its.jnj.com, Wall MJ, Winters MP, Qin N, Lubin ML, Finley MF, Brandt MR, Neeper MP, Schneider CR, Colburn RW, Flores CM, Sui Z
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Jun 15; Vol. 22 (12), pp. 4080-3. Date of Electronic Publication: 2012 May 02.
DOI: 10.1016/j.bmcl.2012.04.075
Abstrakt: 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.)
Databáze: MEDLINE
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