磷酸二酯酶4抑制剂临床及安全性研究进展

Advances in clinical and safety studies of phosphodiesterase 4 inhibitors

磷酸二酯酶4(phosphodiesterase 4,PDE4)是磷酸二酯酶家族中重要成员之一,可特异性水解环磷酸腺苷(cyclic adenosine monophosphate,cAMP),通过改变cAMP浓度引发下游磷酸化级联反应,与多种疾病密切相关。靶向PDE4的抑制剂临床研究包括呼吸系统疾病、自身免疫性疾病、中枢神经系统疾病及皮肤病等多种疾病领域。但是在已上市的PDE4抑制剂临床研究中发现,大多数药物的恶心、呕吐等胃肠道不良反应发生率较高,限制了其临床应用。因此本综述总结了已上市PDE4抑制剂的临床进展及安全性问题,结合PDE4蛋白结构分析、PDE4抑制剂的作用机制及相关不良反应机制研究,阐述了PDE4抑制剂产生不良反应的主要原因,旨在为开发安全有效的PDE4抑制剂提供参考。

Phosphodiesterase 4(PDE4)is an important member of the phosphodiesterase enzyme family that specifically catalyzes the hydrolysis of cyclic adenosine monophosphate(cAMP),activates the downstream phosphorylation cascade pathway by altering cAMP concentration,and is strongly associated with multiple diseases.Inhibition of PDE4 is clinically investigated as a therapeutic strategy in a broad range of disease areas,including respiratory system diseases,autoimmune disorders,central nervous system diseases,and dermatological conditions.However,the incidence of adverse reactions such as nausea and vomiting is relatively high in the marketed PDE4 inhibitors,which has stalled their clinical development.In this review,we provide an overview of the clinical progression and safety issues of the marketed PDE4 inhibitors.We also review the main causes underlying PDE4-mediated adverse effects by combining the structural analysis of the PDE4 protein,the mechanism of action of PDE4 inhibitors,and the related side effect mechanism research,aiming to provide a reference for the development of safe and effective PDE4 inhibitors.