Wu Zongmin, Zhang Furong, Chen Zhexin, Wang Xue, Liu Xingfu, Yang Guofeng, Wang Sen, Huang Shuheng, Luo Hai-Bin, Huang Yi-You, Wu Deyan
Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
School of Life and Health Sciences, Hainan University, Haikou, 570228, China.
Mol Divers. 2025 Jun;29(3):2283-2291. doi: 10.1007/s11030-024-10991-w. Epub 2024 Sep 23.
Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC of 4.78 ± 0.08 μM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC of 0.48 ± 0.02 μM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.
磷酸二酯酶（PDEs）是重要的细胞内酶，可水解第二信使环磷酸腺苷（cAMP）和/或环磷酸鸟苷（cGMP）。目前多项研究表明，PDE4受到特别关注，因为它是参与多种疾病的最主要的cAMP代谢酶。在本研究中，我们对内部化合物库进行了预筛选，发现了具有中等PDE4抑制活性（IC为4.78±0.08 μM）的化合物（PTC-209）。并采用基于结构的发现策略，成功设计并合成了一系列以PTC-209为起始物的新型PDE4抑制剂——4-（咪唑并[1,2-a]嘧啶-3-基）噻唑-2-胺衍生物。最有效的抑制剂L19在大鼠肝微粒体中表现出良好的抑制活性（IC为0.48±0.02 μM）和显著的代谢稳定性。我们的研究展示了发现新型PDE4抑制剂的一个实例，这将有助于未来新型抑制剂的设计和优化。
