喹啉衍生物的合成：发现一种强效和选择性的磷酸二酯酶 5 抑制剂，可用于治疗阿尔茨海默病。
Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease.
机构信息
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.
出版信息
Eur J Med Chem. 2013 Feb;60:285-94. doi: 10.1016/j.ejmech.2012.12.009. Epub 2012 Dec 14.
Abstract
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.
摘要
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。
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本文引用的文献
1
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Br J Pharmacol. 2012 Mar;165(5):1288-305. doi: 10.1111/j.1476-5381.2011.01729.x.
2
Phosphodiesterase-5 inhibitors: novel weapons against Alzheimer's disease?磷酸二酯酶-5 抑制剂：治疗阿尔茨海默病的新武器？
Int J Neurosci. 2010 Dec;120(12):746-51. doi: 10.3109/00207454.2010.520381. Epub 2010 Oct 13.
3
Cyclic GMP and nitric oxide synthase in aging and Alzheimer's disease.环鸟苷酸和一氧化氮合酶与衰老和阿尔茨海默病。
Mol Neurobiol. 2010 Jun;41(2-3):129-37. doi: 10.1007/s12035-010-8104-x. Epub 2010 Mar 9.
4
Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model.磷酸二酯酶5抑制可改善阿尔茨海默病小鼠模型的突触功能、记忆力和β-淀粉样蛋白负荷。
J Neurosci. 2009 Jun 24;29(25):8075-86. doi: 10.1523/JNEUROSCI.0864-09.2009.
5
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Urology. 2009 Apr;73(4):756-61. doi: 10.1016/j.urology.2008.10.058. Epub 2009 Feb 4.
6
Role of phosphodiesterase 5 in synaptic plasticity and memory.磷酸二酯酶 5 在突触可塑性和记忆中的作用。
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10
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