Discovery of phenylisoxazolidine analogs targeting receptor interacting protein kinase 1 with anti-inflammatory...

Receptor Interacting Protein Kinase1 (RIPK1) is a key regulator of necroptosis and plays an important role in various inflammatory signaling and cell death processes. GSK963 has been reported to inhibit RIPK1 with limited anti-necroptotic effect. We designed and prepared a series of phenylisoxazolidine analogs based on GSK963 to improve their anti-necroptotic activity. After several turns of structure activity relationship (SAR) studies, compound 22, encoded with KWML-22, was found to have good anti-necroptotic activity (EC₅₀ = 30.0 nM) and enzymatic activity (IC₅₀ = 6.9 nM) against RIPK1. In a TNF-α-induced inflammation in vivo model, a dose of 10 mg/kg protected mice from hypothermia and death. Our results suggest that 22 is a promising lead compound for the study of inflammatory diseases.