Opportunities and perspectives of small molecular phosphodiesterase inhibitors in neurodegenerative diseases

• Published in: European journal of medicinal chemistry 2024-05, Vol.271, p.116386-116386, Article 116386
• Main Authors: Li, Qi, Liao, Qinghong, Qi, Shulei, Huang, He, He, Siyu, Lyu, Weiping, Liang, Jinxin, Qin, Huan, Cheng, Zimeng, Yu, Fan, Dong, Xue, Wang, Ziming, Han, Lingfei, Han, Yantao
• Format: Article
• Language: English
• Subjects: Neurodegenerative disease; Phosphodiesterase; Small molecule inhibitors
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116386

Phosphodiesterase (PDE) is a superfamily of enzymes that are responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE inhibition promotes the gene transcription by activating cAMP-response element binding protein (CREB), initiating gene transcription of brain-derived neurotrophic factor (BDNF). The procedure exerts neuroprotective profile, and motor and cognitive improving efficacy. From this point of view, PDE inhibition will provide a promising therapeutic strategy for treating neurodegenerative disorders. Herein, we summarized the PDE inhibitors that have entered the clinical trials or been discovered in recent five years. Well-designed clinical or preclinical investigations have confirmed the effectiveness of PDE inhibitors, such as decreasing Aβ oligomerization and tau phosphorylation, alleviating neuro-inflammation and oxidative stress, modulating neuronal plasticity and improving long-term cognitive impairment. [Display omitted] •Biological information of the PDE family accompanied by figures is provided.•The development of diverse PDE inhibitors in recent five years is summarized.•The SAR and therapeutic potential of PDE inhibitors are concluded.•PDEs inhibitors are beneficial for treatment of neurodegenerative diseases.