Discovery of novel 2,8-diazaspiro[4.5]decan-1-one derivatives as potent RIPK1 kinase inhibitors.

ID: ALA5143603

Journal: Bioorg Med Chem

Title: Discovery of novel 2,8-diazaspiro[4.5]decan-1-one derivatives as potent RIPK1 kinase inhibitors.

Authors: Niu A, Lin L, Zhang D, Jiang K, Weng D, Zhou W, Wang J.

Abstract: 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.

CiteXplore: 35228069

DOI: 10.1016/j.bmc.2022.116686

Patent ID: ┄