2. Academic Validation
  3. 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

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. 2026 Jan 15;302(Pt 1):118302. doi: 10.1016/j.ejmech.2025.118302.
Fan Yang 1,  Qi Guo 2,  Mingbin Chen 1,  Wei Wang 1,  Xinyi Chen 1,  Shuting Zhang 1,  Hongyuan Bian 1,  Jinzhuo Li 2,  Ziyi Jiao 1,  Qin Wang 1,  Wandi Xiong 1,  Yi-You Huang 3,  Yajing Liu 4,  Congjun Xu 5,  Ling Huang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
  • 2 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China.
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. Electronic address: [email protected].
  • 4 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, 110016, China. Electronic address: [email protected].
  • 5 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. Electronic address: [email protected].
  • 6 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China. Electronic address: [email protected].
PMID: 41151129 DOI: 10.1016/j.ejmech.2025.118302
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 (IC50 = 0.6 μM, aqueous solubility = 60.36 μg/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t1/2 = 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.

Keywords

2,4,5,6-Tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one; Alzheimer's disease; Drug-likeness; PDE2 inhibitors; Scaffold hopping.

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