Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 W 168th St., New York, NY 10032, USA.
Eur J Med Chem. 2013 Feb;60:285-94. doi: 10.1016/j.ejmech.2012.12.009. Epub 2012 Dec 14.
Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.
磷酸二酯酶 5（PDE5）在包括大脑在内的多种组织中介导 cGMP 的降解。最近的研究表明，一氧化氮/cGMP/cAMP 反应元件结合蛋白（CREB）通路对学习和记忆过程很重要。因此，磷酸二酯酶 5 抑制剂（PDE5Is）被认为是治疗阿尔茨海默病（AD）的有前途的新治疗剂，AD 是一种以记忆丧失为特征的神经退行性疾病。为了探索这种可能性，我们合成并评估了一系列喹啉衍生物。我们发现化合物 7a 选择性地抑制 PDE5，IC50 为 0.27 nM，并且容易穿过血脑屏障。在 AD 的体内小鼠模型中，化合物 7a 挽救了突触和记忆缺陷。基于喹啉的、可穿透中枢神经系统的 PDE5Is 具有 AD 治疗开发的潜力。
