Development of 2‑Methyl-5-phenylpyrrolidine-Based ST2 Inhibitors for Neuroinflammatory Conditions.

The cytokine receptor, ST2, is expressed in immune cells including type 2 T cells, microglia, and astrocytes. ST2 binds with IL-33 to activate the downstream NF-κB pathway. Besides the role of the ST2/IL-33 axis in the expansion of type 2 and regulatory T cells, it mediates the production of pro-inflammatory cytokines by a subset of myeloid cells under inflammatory conditions. Here, we designed and synthesized a new series of ST2 inhibitors by modifying the pyrrolidine core in our previous lead to develop XY-280. Our assessment indicated that XY-280 is the first ST2 inhibitor demonstrating favorable brain-penetration properties, making it a suitable tool for CNS-targeted studies. In the LPS-induced neuroinflammation models, XY-280 significantly attenuated disease-associated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and prostaglandin E2 production in both in vitro and in vivo systems. These findings identify XY-280 as a promising candidate for the ST2 inhibitor development to treat disorders associated with neuroinflammation.