Optimizing metabolic stability of phosphodiesterase 5 inhibitors: Discovery of a potent N-(pyridin-3-ylmethyl)quinoline derivative targeting synaptic plasticity.
Optimizing metabolic stability of phosphodiesterase 5 inhibitors: Discovery of a potent N-(pyridin-3-ylmethyl)quinoline derivative targeting synaptic plasticity.
复制标题
优化磷酸二酯酶 5 抑制剂的代谢稳定性：发现一种针对突触可塑性的有效 N-(吡啶-3-基甲基)喹啉衍生物。
DOI：
10.1016/j.bmcl.2023.129409
复制
发表时间：
2023
影响因子：
2.7
通讯作者：
Fiorito,Jole
中科院分区：
文献类型：
--
作者：
Zuccarello,Elisa;Zhang,Hong;Acquarone,Erica;Pham,Dang;Staniszewski,Anna;Deng,Shi-Xian;Landry,DonaldW;Arancio,Ottavio;Fiorito,Jole
Phosphodiesterase 5 (PDE5) is a cyclic guanosine monophosphate-degrading enzyme involved in numerous biological pathways. Inhibitors of PDE5 are important therapeutics for the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD). We previously reported the first generation of quinoline-based PDE5 inhibitors for the treatment of AD. However, the shortin vitromicrosomal stability rendered them unsuitable drug candidates. Here we report a series of new quinoline-based PDE5 inhibitors. Among them, compound4b, 8-cyclopropyl-3-(hydroxymethyl)-4-(((6-methoxypyridin-3-yl)methyl)amino)quinoline-6-carbonitrile, shows a PDE5 IC50of 20 nM and improvedin vitromicrosomal stability (t1/2= 44.6 min) as well as excellent efficacy in restoring long-term potentiation, a type of synaptic plasticity to underlie memory formation, in electrophysiology experiments with a mouse model of AD. These results provide an insight into the development of a new class of PDE5 inhibitors for the treatment of AD.
