Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama 227-0033, Japan.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4230-4. doi: 10.1016/j.bmcl.2013.05.009. Epub 2013 May 14.
A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke.
合成了一系列新型吡咯烷衍生物作为钠离子通道阻断剂，并评估了它们对神经元钠离子通道的抑制作用。对吡咯烷类似物 2 的构效关系（SAR）研究导致发现 5e 是一种有效的钠离子通道阻断剂，对人 ether-a-go-go-related gene (hERG) 通道的抑制作用较低。化合物 5e 在大鼠短暂性大脑中动脉闭塞（MCAO）模型中表现出显著的神经保护活性，表明 5e 可作为缺血性中风的神经保护剂。
