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Rational Design,Synthesis and Evaluation of Oxazolo[4,5-c]-quinolinone Analogs as Novel Interleukin-33 Inhibitors |
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| Authors: | Yujin Kim Chao Ma Seonghu Park Yujin Shin - Taeyun Lee Jiwon Paek Kyong Hoon Kim Geonhee Jang Haelim Cho Seyoung Son Sang-Hyun Son Prof. Ki Yong Lee Prof. Kiho Lee Prof. Yong Woo Jung Prof. Young Ho Jeon Prof. Youngjoo Byun |
| Affiliation: | 1. College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019 South Korea These authors contributed equally.;2. College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019 South Korea Current address, College of Food & Pharmaceutical Engineering, Guizhou Institute of Technology, Guizhou, 550003 P. R. China These authors contributed equally.;3. College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019 South Korea;4. Department of Biotechnology and Bioinformatics, Korea University, Sejong, 30019 South Korea;5. T&J TECH Inc., 212 Gasan digital 1-ro, Geumcheon-gu, Seoul, 08502 South Korea;6. Azcuris, Co., Ltd., 2511 Sejong-ro, Sejong, 30019 South Korea |
| 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 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. |
| Keywords: | Interleukin-33 Allergy Cytokine Inhibitors Oxazoloquinoline |