Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases.
Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases.
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DOI：
10.3389/fphar.2018.01048
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发表时间：
2018
影响因子：
5.6
通讯作者：
Tang W
中科院分区：
文献类型：
--
作者：
Li H;Zuo J;Tang W
磷酸二酯酶-4（PDE 4）主要存在于免疫细胞、上皮细胞和脑细胞中，表现为调节炎症和上皮完整性的细胞内非受体酶。预计PDE 4的抑制通过环磷酸腺苷（cAMP）水平的升高以及随后对多种基因和蛋白质的调节而具有不同的作用。已经确定PDE 4是用于治疗多种肺部、皮肤病学和严重神经系统疾病的有前景的治疗靶标。在过去的几十年中，已经设计和合成了许多PDE 4抑制剂，其中罗氟司特、阿普斯特和阿司硼分别被批准用于治疗炎性气道疾病、银屑病关节炎和特应性皮炎。令人遗憾的是，一种药物的显著疗效往往伴随着不良反应，如恶心、呕吐和胃肠道反应。然而，在减轻不良反应和获得更好的获益风险比方面取得了实质性进展。本文综述了PDE 4在药物发现中的辩证作用，以及某些PDE 4抑制剂的研究细节，以概述未来仍需解决的问题。
Phosphodiesterase-4 (PDE4), mainly present in immune cells, epithelial cells, and brain cells, manifests as an intracellular non-receptor enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects via the elevation of the level of cyclic adenosine monophosphate (cAMP) and the subsequent regulation of a wide array of genes and proteins. It has been identified that PDE4 is a promising therapeutic target for the treatment of diverse pulmonary, dermatological, and severe neurological diseases. Over the past decades, numerous PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole were approved for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. It is regrettable that the dramatic efficacies of a drug are often accompanied by adverse effects, such as nausea, emesis, and gastrointestinal reactions. However, substantial advances have been made to mitigate the adverse effects and obtain better benefit-to-risk ratio. This review highlights the dialectical role of PDE4 in drug discovery and the disquisitive details of certain PDE4 inhibitors to provide an overview of the topics that still need to be addressed in the future.
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