Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer's Disease.
Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer's Disease.
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作为治疗阿尔茨海默病的新型 PDE2 抑制剂的二氢吡喃吡唑衍生物的设计、合成和评价
DOI：
10.3390/molecules26103034
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发表时间：
2021-05-19
期刊：
影响因子：
--
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Zhou Y;Li J;Yuan H;Su R;Huang Y;Huang Y;Li Z;Wu Y;Luo H;Zhang C;Huang L
磷酸二酯酶2 （PDE2）被认为是治疗阿尔茨海默病（AD）的新靶点。本研究采用基于分子动力学的高通量虚拟筛选方法，获得了具有中等PDE2抑制活性（IC50 = 261.3 nM）的hit化合物(R)-LZ77。然后，我们设计并合成了28个二氢吡喃吡唑衍生物作为PDE2抑制剂。其中化合物(+)-11h是最有效的PDE2抑制剂，IC50值为41.5 nM。PDE2-（+)-11h的分子对接表明，化合物的4-（三氟甲基）苄基）氧侧链进入H-pocket，与L770/L809/F862形成强疏水相互作用，提高了抑制活性。上述结果可能为进一步优化高效PDE2抑制剂的结构提供见解，并可能为其在AD治疗中的应用奠定基础。
Phosphodiesterase 2 (PDE2) has been regarded as a novel target for the treatment of Alzheimer’s disease (AD). In this study, we obtained (R)-LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC50 = 261.3 nM) using a high-throughput virtual screening method based on molecular dynamics. Then, we designed and synthesized 28 dihydropyranopyrazole derivatives as PDE2 inhibitors. Among them, compound (+)-11h was the most potent PDE2 inhibitor, with an IC50 value of 41.5 nM. The molecular docking of PDE2-(+)-11h reveals that the 4-(trifluoromethyl)benzyl)oxyl side chain of the compound enters the H-pocket and forms strong hydrophobic interactions with L770/L809/F862, which improves inhibitory activity. The above results may provide insight for further structural optimization of highly potent PDE2 inhibitors and may lay the foundation for their use in the treatment of AD.
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