Novel Phosphodiesterase Inhibitors for Cognitive Improvement in Alzheimer's Disease
Novel Phosphodiesterase Inhibitors for Cognitive Improvement in Alzheimer's Disease
复制标题
DOI：
10.1021/acs.jmedchem.7b01370
复制
发表时间：
2018-07-12
影响因子：
7.3
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Wu, Yinuo;Li, Zhe;Luo, Hai-Bin
阿尔茨海默病（AD）是最大的公共卫生挑战之一。磷酸二酯酶（PDEs）是一个超酶家族，负责水解两个第二信使：环腺苷单磷酸（cAMP）和环鸟苷单磷酸（cGMP）。由于几个PDE亚家族在人脑中高度表达，PDE的抑制可能通过调节cAMP和/或cGMP的浓度参与神经退行性过程。目前，PDE被认为是治疗AD的有希望的靶点，因为许多PDE抑制剂在临床前研究中表现出显着的认知改善效果，其中超过15种已进入临床试验。本综述的目的是总结PDE抑制剂作为抗ad药物在临床前研究和临床试验中取得的令人鼓舞的进展。本文还对这些PDE抑制剂治疗AD的结合亲和力、药代动力学、潜在机制和局限性进行了综述和讨论。
Alzheimer's disease (AD) is one of the greatest public health challenges. Phosphodiesterases (PDEs) are a superenzyme family responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Since several PDE subfamilies are highly expressed in the human brain, the inhibition of PDEs is involved in neurodegenerative processes by regulating the concentration of cAMP and/or cGMP. Currently, PDEs are considered as promising targets for the treatment of AD since many PDE inhibitors have exhibited remarkable cognitive improvement effects in preclinical studies and over 15 of them have been subjected to clinical trials. The aim of this review is to summarize the outstanding progress that has been made by PDE inhibitors as anti-AD agents with encouraging results in preclinical studies and clinical trials. The binding affinity, pharmacokinetics, underlying mechanisms, and limitations of these PDE inhibitors in the treatment of AD are also reviewed and discussed.