Design, synthesis, and structure-activity relationship studies of 6,7-dihydro-5-pyrrolo[1,2-][1,2,4]triazole derivatives as necroptosis inhibitors

The development of necroptosis inhibitors has emerged as a promising strategy to effectively mitigate necroptosis-related inflammatory diseases, neurodegenerative diseases, and cancers. In this paper, we reported a series of 6,7-dihydro-5 H -pyrrolo[1,2- b ][1,2,4]triazole derivatives as potent necroptosis inhibitors. The representative compound 26 displayed potent anti-necroptotic activity in both human and mouse cellular assays and exhibited potent inhibitory activity against receptor-interacting protein kinase 1 (RIPK1). In vivo pharmacokinetic studies were performed to determine the oral exposure of compound 26 . Finally, molecular docking elucidated that compound 26 could effectively bind to the allosteric pocket of RIPK1 and serve as a type III inhibitor. Taken together, our findings highlighted that compound 26 represented a promising lead compound for future necroptosis inhibitor development. This study reported a series of 6,7-dihydro-5 H -pyrrolo[1,2- b ][1,2,4]triazole derivatives with potent RIPK1 inhibitory activity and anti-necroptotic activity in both human and mouse cellular assays.