Phosphodiesterases (PDEs) have been an interesting drug target for many diseases. Although a vast number of mainly preclinical studies demonstrates beneficial effects of PDE inhibitors for central nervous system (CNS) diseases, no drugs are currently available for CNS indications. In this review, we discuss the rationale of PDE4 inhibitors for different CNS diseases, including memory impairments, striatal disorders, multiple sclerosis (MS), and acquired brain injury (ABI). However, clinical development has been problematic due to mechanism-based adverse effects of these drugs in humans. Our increased understanding of factors influencing the conformational state of the PDE4 enzyme and of how to influence the binding affinity of PDE4 subtype inhibitors, holds promise for the successful development of novel selective PDE4 inhibitors with higher efficacy and fewer adverse effects.

中文翻译：

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中枢神经系统疾病中的磷酸二酯酶4型抑制作用。

磷酸二酯酶（PDEs）已成为许多疾病的有趣药物靶标。尽管大量的主要临床前研究表明PDE抑制剂对中枢神经系统（CNS）疾病具有有益作用，但目前尚无可用于CNS适应症的药物。在这篇综述中，我们讨论了PDE4抑制剂针对不同中枢神经系统疾病的基本原理，包括记忆障碍，纹状体疾病，多发性硬化症（MS）和获得性脑损伤（ABI）。然而，由于这些药物对人体的基于机理的不良反应，临床开发存在问题。我们对影响PDE4酶构象状态的因素以及如何影响PDE4亚型抑制剂的结合亲和力的了解不断加深，