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

  • Bioorg Med Chem. 2022 Apr 1;59:116686. doi: 10.1016/j.bmc.2022.116686.
Ao Niu  1 ,  Lizhi Lin  1 ,  Danyang Zhang  2 ,  Kaixuan Jiang  1 ,  Dan Weng  2 ,  Wenjia Zhou  3 ,  Jinxin Wang  4
Affiliations
  • 1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
  • 2. School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, China.
  • 3. Department of Clinical Pharmacology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China. Electronic address: [email protected].
  • 4. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China. Electronic address: [email protected].
PMID: 35228069 DOI: 10.1016/j.bmc.2022.116686
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.

Keywords
Necroptosis; RIPK1 inhibitor; Structure–activity relationship (SAR); Virtual screening.
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