Li Heng, Zuo Jianping, Tang Wei
Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China.
Front Pharmacol. 2018 Oct 17;9:1048. doi: 10.3389/fphar.2018.01048. eCollection 2018.
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.
磷酸二酯酶4（PDE4）主要存在于免疫细胞、上皮细胞和脑细胞中，是一种细胞内非受体酶，可调节炎症和上皮完整性。预计抑制PDE4会通过提高环磷酸腺苷（cAMP）水平以及随后对一系列基因和蛋白质的调节而产生多种作用。已确定PDE4是治疗多种肺部、皮肤病和严重神经疾病的有前景的治疗靶点。在过去几十年中，已设计并合成了许多PDE4抑制剂，其中罗氟司特、阿普斯特和克立硼罗分别被批准用于治疗炎症性气道疾病、银屑病关节炎和特应性皮炎。遗憾的是，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效益风险比方面已取得了重大进展。本综述强调了PDE4在药物发现中的辩证作用以及某些PDE4抑制剂的研究细节，以概述未来仍需解决的问题。
