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
  • 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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