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. Epub 2022 Feb 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Spiro Compounds* / chemistry
  • Spiro Compounds* / pharmacology

Substances

  • Aza Compounds
  • Protein Kinase Inhibitors
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • RIPK1 protein, human
  • Spiro Compounds
  • 2,8-diazaspiro(4.5)decan-1-one