Rational Design, Synthesis and Evaluation of Oxazolo[4,5-c]-quinolinone Analogs as Novel Interleukin-33 Inhibitors

Chem Asian J. 2021 Nov 15;16(22):3702-3712. doi: 10.1002/asia.202100896. Epub 2021 Sep 28.

Abstract

Interleukin-33 (IL-33) is an epithelial-derived cytokine that plays an important role in immune-mediated diseases such as asthma, atopic dermatitis, and rheumatoid arthritis. Although IL-33 is considered a potential target for the treatment of allergy-related diseases, no small molecule that inhibits IL-33 has been reported. Based on the structure-activity relationship and in vitro 2D NMR studies employing 15 N-labeled IL-33, we identified that the oxazolo[4,5-c]-quinolinone analog 7 c binds to the interface region of IL-33 and IL-33 receptor (ST2), an orphan receptor of the IL-1 receptor family. Compound 7 c effectively inhibited the production of IL-6 in human mast cells in a dose-dependent manner. Compound 7 c is the first low molecular weight IL-33 inhibitor and may be used as a prototype molecule for structural optimization and investigation of the IL-33/ST2 signaling pathway.

Keywords: Allergy; Cytokine; Inhibitors; Interleukin-33; Oxazoloquinoline.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein / antagonists & inhibitors
  • Interleukin-33 / antagonists & inhibitors*
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / biosynthesis
  • Mast Cells / drug effects
  • Mast Cells / metabolism
  • Molecular Structure
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / pharmacology*

Substances

  • IL33 protein, human
  • IL6 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukin-6
  • Quinolones