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首页> 外文期刊>Biochemical Pharmacology >Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer's disease
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Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer's disease

机译：新型磷酸二酯酶5抑制剂的开发，用于治疗阿尔茨海默病的治疗

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摘要

Nitric oxide (NO) is a gaseous molecule that plays a multifactorial role in several cellular processes. In the central nervous system, the NO dual nature in neuroprotection and neurotoxicity has been explored to unveil its involvement in Alzheimer's disease (AD). A growing body of research shows that the activation of the NO signaling pathway leading to the phosphorylation of the transcription factor cyclic adenine monophosphate responsive element binding protein (CREB) (so-called NO/cGMP/PKG/CREB signaling pathway) ameliorates altered neuroplasticity and memory deficits in AD animal models. In addition to NO donors, several other pharmacological agents, such as phosphodiesterase 5 (PDE5) inhibitors have been used to activate the pathway and rescue memory disorders. PDE5 inhibitors, including sildenafil, tadalafil and vardenafil, are marketed for the treatment of erectile dysfunction and arterial pulmonary hypertension due to their vasodilatory properties. The ability of PDE5 inhibitors to interfere with the NO/cGMP/PKG/CREB signaling pathway by increasing the levels of cGMP has prompted the hypothesis that PDE5 inhibition might be used as an effective therapeutic strategy for the treatment of AD. To this end, newly designed PDE5 inhibitors belonging to different chemical classes with improved pharmacologic profile (e.g. higher potency, improved selectivity, and blood-brain barrier penetration) have been synthesized and evaluated in several animal models of AD. In addition, recent medicinal chemistry effort has led to the development of agents concurrently acing on the PDE5 enzyme and a second target involved in AD. Both marketed and investigational PDE5 inhibitors have shown to reverse cognitive defects in young and aged wild type mice as well as transgenic mouse models of AD and tauopathy using a variety of behavioral tasks. These studies confirmed the therapeutic potential of PDE5 inhibitors as cognitive enhancers. However, clinical studies assessing cognitive functions using marketed PDE5 inhibitors have not been conclusive. Drug discovery efforts by our group and others are currently directed towards the development of novel PDE5 inhibitors tailored to AD with improved pharmacodynamic and pharmacokinetic properties. In summary, the present perspective reports an overview of the correlation between the NO signaling and AD, as well as an outline of the PDE5 inhibitors used as an alternative approach in altering the NO pathway leading to an improvement of learning and memory. The last two sections describe the preclinical and clinical evaluation of PDE5 inhibitors for the treatment of AD, providing a comprehensive analysis of the current status of the AD drug discovery efforts involving PDE5 as a new therapeutic target.
机译：一氧化氮（NO）是在几种细胞过程中发挥多学会作用的气态分子。在中枢神经系统中，已经探讨了神经保护和神经毒性的双重性，以揭示其参与阿尔茨海默病（AD）。越来越多的研究表明，无信号通路的激活导致转录因子环状腺嘌呤单磷酸响应元结合蛋白（CREB）（所谓的NO / CGMP / PKG / CREB信号通路）改善改变的神经塑性和广告动物模型中的内存缺陷。除了没有供体外，还用于激活途径和救援记忆障碍的其他几种其他药物试剂。 PDE5抑制剂，包括西地那非，塔达拉非（Tadalafil和Vardenafil，由于其血管舒张性能而销售用于治疗勃起功能障碍和动脉肺动脉高压。通过增加CGMP水平的PDE5抑制剂干扰NO / CGMP / PKG / CREB信号传导途径的能力促使PDE5抑制可作为治疗广告治疗的有效治疗策略的假设。为此，新设计的PDE5抑制剂属于不同的化学类，具有改善的药理学曲线（例如效力较高，改善的选择性和血脑屏障渗透），并在若干广告的动物模型中进行了合成和评估。此外，最近的药用化学努力导致了在PDE5酶和AD中涉及的第二个靶向上同时进行的药剂的发育。销售和调查的PDE5抑制剂都显示出使用各种行为任务的年轻和老化野生型小鼠的认知缺陷以及AD和Tauoxathy的转基因小鼠模型。这些研究证实了PDE5抑制剂作为认知增强剂的治疗潜力。然而，评估使用销售PDE5抑制剂的认知功能的临床研究尚未结论。我们的小组和其他人目前针对具有改进的药效学和药代动力学性质的广告抑制剂的新型PDE5抑制剂的开发。总之，目前的透视报告了NO信令和广告之间的相关性的概述，以及用作改变NO路径的替代方法的PDE5抑制剂的概要，导致学习和记忆的改善。最后两部分描述了PDE5抑制剂用于治疗广告的临床前和临床评价，提供了综合分析了涉及PDE5作为新治疗目标的广告药物发现努力的现状。

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