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

• Published in: Bioorganic & medicinal chemistry 2022-04, Vol.59, p.116686-116686, Article 116686
• Main Authors: Niu, Ao, Lin, Lizhi, Zhang, Danyang, Jiang, Kaixuan, Weng, Dan, Zhou, Wenjia, Wang, Jinxin
• Format: Article
• Language: English
• Subjects: Apoptosis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Humans; Necroptosis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - pharmacology; RIPK1 inhibitor; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure–activity relationship (SAR); Virtual screening
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2022.116686

[Display omitted] 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.