Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):4080-3. doi: 10.1016/j.bmcl.2012.04.075. Epub 2012 May 2.
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.
选择性 N 型钙通道阻滞剂已被证明在慢性疼痛的动物模型中有效。然而，尽管从 Conus magnus（芋螺毒素 MVIIA [Prialt®]）鞘内给予合成的 ω-芋螺毒素 MVIIA 已被批准用于治疗人类慢性疼痛，但它的给药方式和狭窄的治疗窗口限制了其用途。因此，鉴定出具有口服活性的小分子 N 型钙通道阻滞剂将代表在治疗慢性疼痛方面的重大进展。通过对高通量筛选命中物进行结构修饰，确定了一系列新型基于吡唑的 N 型钙通道阻滞剂，并进一步优化以提高效力和代谢稳定性。该系列的代表性化合物在大鼠炎症和神经性疼痛模型中证明了体内疗效。
