Structure-based design, synthesis, and biological evaluation of novel pyrimidinone derivatives as PDE9 inhibitors

• 来源期刊: 药学学报（英文版）
• 关键词: PDE9 inhibitors Alzheimer's disease Type 2 diabetes mellitus Rosiglitazone Molecular docking Dynamics simulation
• 年，卷（期）: 2018,（4）
• 页码范围: 615-628
• 页数: 14页
• 语种: 英文

摘要

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC50 values o5 nmol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound 11a, the most effective one, gave the IC50 of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The analysis of putative binding patterns and binding free energy of the designed compounds with PDE9 may explain the structure– activity relationships and provide evidence for further structural modifications.