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Due to the crucial role of receptor\u2010interacting protein kinase 1 (RIPK1) in the necroptosis pathway, RIPK1 inhibitors are believed to have great potential in the treatment of necroptosis\u2010related diseases. In this article, we reported a series of pyridazin\u20104\u2010one derivatives as potent necroptosis inhibitors for both human and mouse cells. The representative compound <jats:bold>13<\/jats:bold> exhibited favorable RIPK1 selectivity and dose\u2010dependently inhibited RIPK1 phosphorylation. The in vivo pharmacokinetic study indicated that compound <jats:bold>13<\/jats:bold> was an orally available candidate. Finally, molecular docking and molecular dynamics simulations were performed to elucidate the binding pattern of compound <jats:bold>13<\/jats:bold> with RIPK1. Collectively, compound <jats:bold>13<\/jats:bold> represents a promising lead compound for the future development of RIPK1\u2010targeted necroptosis inhibitors.<\/jats:p>","DOI":"10.1002\/ardp.202400594","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T06:12:52Z","timestamp":1732255972000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and synthesis of pyridazin\u20104\u2010one derivatives as necroptosis inhibitors"],"prefix":"10.1002","volume":"358","author":[{"given":"Yuxiang","family":"An","sequence":"first","affiliation":[{"name":"Small\u2010Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM) Chinese Academy of Sciences Shanghai China"},{"name":"School of Pharmacy University of Chinese Academy of Sciences Beijing 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