9WP3

The crystal structure of PDE2A complexed with inhibitor 13j

これはPDB形式変換不可エントリーです。

9WP3 の概要

• エントリーDOI: 10.2210/pdb9wp3/pdb
• 分子名称: cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pde2a inhibitor, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 160878.66

構造登録者

Huang, Y.-Y.,Luo, H.-B. (登録日: 2025-09-08, 公開日: 2026-02-18)

主引用文献

Yang, F.,Guo, Q.,Chen, M.,Wang, W.,Chen, X.,Zhang, S.,Bian, H.,Li, J.,Jiao, Z.,Wang, Q.,Xiong, W.,Huang, Y.Y.,Liu, Y.,Xu, C.,Huang, L.
Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential.
Eur.J.Med.Chem., 302:118302-118302, 2026

PubMed Abstract: Phosphodiesterase 2 (PDE2), a dual-substrate cyclic nucleotide hydrolase, represents a potential therapeutic target for cognitive impairment. This study aims to develop 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one-based PDE2 inhibitors with favorable drug-like properties for the treatment of Alzheimer's disease. Through scaffold hopping and cocrystal structure analysis, compound 14c was identified as an effective PDE2 inhibitor (IC = 0.6 μM, aqueous solubility = 60.36 μg/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t = 4.4 h, F% = 95.66 %) and promising safety both in vitro and in vivo. In the OKA-induced AD mice models, administration of 14c significantly improved memory deficits and cognitive impairment. Molecular mechanism studies revealed that the neuroprotective effects of 14c were mediated through the PKA/CREB/BDNF signaling pathway. Collectively, these findings represent significant advances in developing PDE2 inhibitors with favorable drug-like properties and establish a solid foundation for their therapeutic application in AD.

PubMed: 41151129
DOI: 10.1016/j.ejmech.2025.118302

実験手法

X-RAY DIFFRACTION (2.50183917707 Å)