Rational Design, Synthesis and Evaluation of Oxazolo[4,5‐ c ]‐quinolinone Analogs as Novel Interleukin‐33 Inhibitors
- 22 September 2021
- journal article
- research article
- Published by Wiley in Chemistry – An Asian Journal
- Vol. 16 (22), 3702-3712
- https://doi.org/10.1002/asia.202100896
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 7c binds to the interface region of IL-33 and IL-33 receptor (ST2), an orphan receptor of the IL-1 receptor family. Compound 7c effectively inhibited the production of IL-6 in human mast cells in a dose-dependent manner. Compound 7c 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
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