Interleukin-33 (IL-33) is a member of the IL-1 superfamily that plays an important role in immune-mediated diseases such as asthma, atopic dermatitis, and rheumatoid arthritis. IL-33 drives the expression of Th2 cytokines and regulates immune responses by binding to ST2 receptor, an orphan receptor of the IL-1 receptor family. Although IL-33 was identified as a ligand for ST2, no small molecule inhibitors to block the interaction of IL-33 and ST2 have been reported. We previously reported that 2-phenyl-5H-[1,3]oxazolo [4,5-c]quinolin-4-one binds to the hydrophobic pocket of IL-33 at 2D NMR studies, thus, might block the interaction between IL-33 and ST2. Novel fifteen oxazolo [4,5-c]quinolin-4-one analogs were synthesized in 6 steps with 9% overall yield. Alkylation at the final step provided a mixture of O- and N-alkylated products. Most of the final compounds interacted with the amino acid residues in the interface region of IL-33 with ST2 at the 2D NMR studies. The O-alkylated analog 7c was the most potent one with an IC50 value of 70 nM at cell-based ELISA assay. It also reduced eosinophil recruitment to the lung at in vivo experiment with ovalbumin-challenged mouse model. To improve synthetic yield for 7c, we established an alternative route which provided the final compound (~16% overall yield) with exclusive O-alkylation. Compound 7c can be utilized as a template compound for structural optimization and as a tool compound for investigating the IL-33/ST2 signaling pathway.

Rational design and synthesis of novel inhibitors specific for interleukin-33

2019 Fall National Meeting

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