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

• Published in: Chemistry, an Asian journal Vol. 16; no. 22; pp. 3702 - 3712
• Main Authors: Kim, Yujin, Ma, Chao, Park, Seonghu, Shin ‐, Yujin, Lee, Taeyun, Paek, Jiwon, Hoon Kim, Kyong, Jang, Geonhee, Cho, Haelim, Son, Seyoung, Son, Sang‐Hyun, Yong Lee, Ki, Lee, Kiho, Woo Jung, Yong, Ho Jeon, Young, Byun, Youngjoo
• Format: Journal Article
• Language: English
• Published: Germany 15.11.2021
• Subjects: Allergy; Cytokine; Dose-Response Relationship, Drug; Drug Design; Humans; Inhibitors; Interleukin-1 Receptor-Like 1 Protein - antagonists & inhibitors; Interleukin-33; Interleukin-33 - antagonists & inhibitors; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - biosynthesis; Mast Cells - drug effects; Mast Cells - metabolism; Molecular Structure; Oxazoloquinoline; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Oxazoloquinoline; Allergy; Inhibitors; Interleukin-33; Cytokine
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.202100896

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 15N‐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. The oxazolo[4,5‐c]‐quinolinone analog 7 c is the first small‐molecule inhibitor of interleukin‐33, demonstrated by its binding to the interface of IL‐33 and ST2 in a 2D NMR study and a strong inhibition of interleukin‐6 production in human mast cells.