Discovery of a 1H-Pyrazol-3-Amine Derivative as a Novel, Selective, and Orally Available RIPK1 Inhibitor for the Treatment of Inflammatory Disease.

Receptor-interacting protein kinase 1 (RIPK1) undergoes aberrant activation during the process of cell necroptosis, thereby facilitating and intensifying the inflammatory response. The inhibition of RIPK1 kinase activity is regarded as a promising therapeutic target for immune-mediated inflammatory diseases that are associated with necroptosis. Herein, we present the structural optimization and investigation into the structure-activity relationship of a series of 1H-pyrazol-3-amine derivatives, derived from the clinical-stage FGFR inhibitor AZD4547. The prioritized compound 44 displayed low nanomolar activity against RIPK1 and had a potent protective effect against necroptosis in both human and murine cells in vitro. In addition to high kinome selectivity, the compound also possessed favorable pharmacokinetic properties, with high AUC and oral bioavailability. Furthermore, 44 showed good therapeutic effects in both TNF-α-induced systemic inflammatory response syndrome and DSS-induced inflammatory bowel disease models in vivo. In summary, 44 is a promising lead compound for RIPK1 inhibition and warrants further study.