Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Bioorg Med Chem Lett. 2009 Nov 15;19(22):6467-72. doi: 10.1016/j.bmcl.2009.09.008. Epub 2009 Sep 11.
The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type calcium channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium channel.
治疗药物氟桂利嗪和洛美利嗪对多种离子通道和神经递质受体具有抑制活性。我们对它们的支架进行了优化，以获得更具选择性的 N 型钙通道阻滞剂。在这个优化过程中，我们发现了 NP118809 和 NP078585，这两种强效的 N 型钙通道阻滞剂对 L 型钙通道具有良好的选择性。在腹腔给药后，这两种化合物在炎症性疼痛的啮齿动物模型中均表现出镇痛活性。NP118809 还表现出许多与整体药代动力学和最小的脱靶活性相关的有利的临床前特征，包括 hERG 钾通道。
