{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T03:17:11Z","timestamp":1771816631886,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023T160663"],"award-info":[{"award-number":["2023T160663"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. The development of necroptosis inhibitors may offer a promising therapeutic strategy for the treatment of these autoimmune diseases. Herein, starting from the in\u2010house hit compound <jats:bold>1<\/jats:bold>, we systematically performed structural optimization to discover potent necroptosis inhibitors with good pharmacokinetic profiles. The resulting compound <jats:bold>33<\/jats:bold> was a potent necroptosis inhibitor for both human I2.1 cells (IC<jats:sub>50<\/jats:sub>\u2009&lt;\u20090.2\u2009nM) and murine Hepa1\u20106 cells (IC<jats:sub>50<\/jats:sub>\u2009&lt;\u20095\u2009nM). Further target identification revealed that compound <jats:bold>33<\/jats:bold> was an inhibitor of receptor interacting protein kinase 1 (RIPK1) with favorable selectivity. In addition, compound <jats:bold>33<\/jats:bold> also exhibited favorable pharmacokinetic profiles (<jats:italic>T<\/jats:italic><jats:sub>1\/2<\/jats:sub>\u2009=\u20091.32\u2009h, AUC\u2009=\u20091157\u2009ng\u00b7h\/mL) in Sprague\u2010Dawley rats. Molecular docking and molecular dynamics simulations confirmed that compound <jats:bold>33<\/jats:bold> could bind to RIPK1 with high affinity. In silico ADMET analysis demonstrated that compound <jats:bold>33<\/jats:bold> possesses good drug\u2010likeness profiles. Collectively, compound <jats:bold>33<\/jats:bold> is a promising candidate for antinecroptotic drug discovery.<\/jats:p>","DOI":"10.1002\/ardp.202400302","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T02:16:16Z","timestamp":1719972976000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery and optimization of 3\u2010(indolin\u20105\u2010yloxy)pyridin\u20102\u2010amine derivatives as potent necroptosis inhibitors"],"prefix":"10.1002","volume":"357","author":[{"given":"Yaohan","family":"Lan","sequence":"first","affiliation":[{"name":"Small\u2010Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM) Chinese Academy of Sciences Shanghai China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinchun","family":"Ji","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Shanghai Institute of Materia Medica (SIMM) Chinese Academy of Sciences Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Peng","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Shanghai Institute of Materia Medica (SIMM) Chinese Academy of Sciences Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhu","family":"Duan","sequence":"additional","affiliation":[{"name":"Small\u2010Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM) Chinese Academy of Sciences Shanghai China"},{"name":"University of Chinese Academy of Sciences Beijing China"},{"name":"Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug Discovery Yantai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiyu","family":"Geng","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences Beijing China"},{"name":"Cancer Research Center, Shanghai Institute of Materia Medica (SIMM) Chinese Academy of Sciences Shanghai China"},{"name":"Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug Discovery Yantai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Ai","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences Beijing China"},{"name":"Cancer Research Center, Shanghai Institute of Materia Medica (SIMM) Chinese Academy of Sciences Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7816-7076","authenticated-orcid":false,"given":"Hefeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Small\u2010Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM) Chinese Academy of Sciences Shanghai 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