Rational Design, Synthesis and Evaluation of Oxazolo[4,5‐<i>c</i>]‐quinolinone Analogs as Novel Interleukin‐33 Inhibitors
Yujin Kim, Chao Ma, Seonghu Park, Yujin Shin ‐, Taeyun Lee, Jiwon Paek, Kyong Hoon Kim, Geonhee Jang, Haelim Cho, Se-Young Son, Sang‐Hyun Son, Ki Yong Lee, Kiho Lee, Yong Woo Jung, Young Ho Jeon, Youngjoo Byun
Abstract
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.