Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, China.
Bioorg Med Chem. 2022 Apr 1;59:116686. doi: 10.1016/j.bmc.2022.116686. Epub 2022 Feb 23.
Necroptosis, a key form of programmed lytic cell death, has gained recognition as an important driver in various inflammatory diseases. Inhibition of kinase activity of receptor interaction protein kinase 1 (RIPK1), which block the activation of the necroptosis pathway has shown therapeutic potential in many human diseases. In order to find new chemotypes of RIPK1 inhibitors, a virtual screening workflow was performed and led to the discovery of 8-benzoyl-3-benzyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (compound 8) as a hit compound. Further structural optimization identified a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as potent RIPK1 inhibitors. Among them, compound 41 exhibited prominent inhibitory activity against RIPK1 with an IC value of 92 nM. Meanwhile, compound 41 showed a significant anti-necroptotic effect in a necroptosis model in U937 cells. Therefore, compound 41 could be employed as a lead compound of RIPK1 inhibitors for further structural optimization.
细胞程序性坏死（Necroptosis）是一种关键的溶酶体细胞死亡形式，它已被认为是多种炎症性疾病的重要驱动因素。抑制受体相互作用蛋白激酶 1（RIPK1）的激酶活性可以阻断细胞程序性坏死途径的激活，这在许多人类疾病中显示出了治疗潜力。为了寻找新的 RIPK1 抑制剂化学型，我们进行了虚拟筛选工作流程，从而发现了 8-苯甲酰基-3-苄基-1,3,8-三氮杂螺[4.5]癸烷-2,4-二酮（化合物 8）作为一个先导化合物。进一步的结构优化确定了一系列 2,8-二氮杂螺[4.5]癸烷-1-酮衍生物作为有效的 RIPK1 抑制剂。其中，化合物 41 对 RIPK1 表现出突出的抑制活性，IC 值为 92 nM。同时，化合物 41 在 U937 细胞的细胞程序性坏死模型中表现出显著的抗细胞程序性坏死作用。因此，化合物 41 可作为 RIPK1 抑制剂的先导化合物进一步进行结构优化。
