Therapeutic potential of phosphodiesterase inhibitors for cognitive amelioration in Alzheimer's disease

Meiyang Xi; Tianyu Sun; Shejie Chai; Mengjiao Xie; Siqi Chen; Liping Deng; Kui Du; Runpu Shen; Haopeng Sun

doi:10.1016/j.ejmech.2022.114170

Therapeutic potential of phosphodiesterase inhibitors for cognitive amelioration in Alzheimer's disease

Eur J Med Chem. 2022 Mar 15:232:114170. doi: 10.1016/j.ejmech.2022.114170. Epub 2022 Feb 3.

Authors

Meiyang Xi¹, Tianyu Sun², Shejie Chai³, Mengjiao Xie⁴, Siqi Chen⁴, Liping Deng¹, Kui Du¹, Runpu Shen⁵, Haopeng Sun⁶

Affiliations

¹ College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China; Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing, 312000, China.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
³ Beida Pharmaceutical Co. Ltd., Hangzhou, 310000, China.
⁴ College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China.
⁵ College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China; Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing, 312000, China. Electronic address: srunpu@usx.edu.cn.
⁶ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: sunhaopeng@163.com.

PMID: 35144038
DOI: 10.1016/j.ejmech.2022.114170

Abstract

Alzheimer's disease (AD), one of the greatest threats to human health, is characterized by declined cognition and changed behavior. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that play an important role in learning and memory are hydrolyzed by phosphodiesterases (PDEs). Most PDE isoforms are highly expressed in the brain, and the inhibition of PDEs is beneficial to counteract AD. Thus, targeting PDEs represents a therapeutic potential for this disease. So far, a variety of PDE inhibitors have been discovered with significant cognitive enhancement effects in animal models and more than ten agents have entered into clinical trials. In this review, we summarize PDE mediated cyclic nucleotide signaling pathways, PDE family members involved in AD and recent advance of PDE inhibitors in preclinical and clinical studies, trying to provide an outlook of PDE inhibitors for the treatment of AD in future.

Keywords: AD; Cognition; PDE inhibitors; Selectivity.

Publication types

Review

MeSH terms

3',5'-Cyclic-AMP Phosphodiesterases / metabolism
Alzheimer Disease* / drug therapy
Animals
Cognition
Cyclic GMP / pharmacology
Phosphodiesterase Inhibitors* / pharmacology
Phosphodiesterase Inhibitors* / therapeutic use
Phosphoric Diester Hydrolases / metabolism

Substances

Phosphodiesterase Inhibitors
Phosphoric Diester Hydrolases
3',5'-Cyclic-AMP Phosphodiesterases
Cyclic GMP