Discovery of a 1 <i>H</i> -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 1<i>H</i>-pyrazol-3-amine derivatives, derived from the clinical-stage FGFR inhibitor AZD4547. The prioritized compound <b>44</b> displayed low nanomolar activity against RIPK1 and had a potent protective effect against necroptosis in both human and murine cells <i>in vitro</i>. In addition to high kinome selectivity, the compound also possessed favorable pharmacokinetic properties, with high AUC and oral bioavailability. Furthermore, <b>44</b> showed good therapeutic effects in both TNF-α-induced systemic inflammatory response syndrome and DSS-induced inflammatory bowel disease models <i>in vivo</i>. In summary, <b>44</b> is a promising lead compound for RIPK1 inhibition and warrants further study.