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 IC₅₀ 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.

坏死性凋亡是程序性裂解细胞死亡的一种关键形式，已被认为是各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) 的激酶活性可阻断坏死性凋亡途径的激活，已在许多人类疾病中显示出治疗潜力。为了寻找 RIPK1 抑制剂的新化学型，进行了虚拟筛选工作流程并发现了 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 ) 作为热门化合物。进一步的结构优化确定了一系列 2,8-diazaspiro[4.5]decan-1-one 衍生物作为有效的 RIPK1 抑制剂。其中，化合物41对RIPK1表现出显着的抑制活性，IC ₅₀值为92 nM。同时，化合物41在U937细胞坏死性凋亡模型中显示出显着的抗坏死性凋亡作用。因此，化合物41可以作为RIPK1抑制剂的先导化合物进行进一步的结构优化。