9wp3
The crystal structure of PDE2A complexed with inhibitor 13j
Structural highlights
FunctionPDE2A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[1] [2] Publication Abstract from PubMedPhosphodiesterase 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(50) = 0.6 muM, aqueous solubility = 60.36 mug/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t(1/2) = 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. 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.,Yang F, Guo Q, Chen M, Wang W, Chen X, Zhang S, Bian H, Li J, Jiao Z, Wang Q, Xiong W, Huang YY, Liu Y, Xu C, Huang L Eur J Med Chem. 2026 Jan 15;302(Pt 1):118302. doi: 10.1016/j.ejmech.2025.118302. , Epub 2025 Oct 24. PMID:41151129[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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