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Discovery of novel 2,8-diazaspiro[4.5]decan-1-one derivatives as potent RIPK1 kinase inhibitors.
Niu, Ao; Lin, Lizhi; Zhang, Danyang; Jiang, Kaixuan; Weng, Dan; Zhou, Wenjia; Wang, Jinxin.
Afiliación
  • Niu A; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
  • Lin L; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
  • Zhang D; School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, China.
  • Jiang K; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
  • Weng D; School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing 210094, China.
  • Zhou W; Department of Clinical Pharmacology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China. Electronic address: zwjaja@163.com.
  • Wang J; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China. Electronic address: jinxinwangcpu@126.com.
Bioorg Med Chem ; 59: 116686, 2022 04 01.
Article en En | MEDLINE | ID: mdl-35228069
Necroptosis, a key form of programmed lytic cell death, has gained recognition as an important driver in various inflammatory diseases. Inhibition of kinase activity of receptor interaction protein kinase 1 (RIPK1), which block the activation of the necroptosis pathway has shown therapeutic potential in many human diseases. In order to find new chemotypes of RIPK1 inhibitors, a virtual screening workflow was performed and led to the discovery of 8-benzoyl-3-benzyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (compound 8) as a hit compound. Further structural optimization identified a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as potent RIPK1 inhibitors. Among them, compound 41 exhibited prominent inhibitory activity against RIPK1 with an IC50 value of 92 nM. Meanwhile, compound 41 showed a significant anti-necroptotic effect in a necroptosis model in U937 cells. Therefore, compound 41 could be employed as a lead compound of RIPK1 inhibitors for further structural optimization.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Espiro / Compuestos Aza / Inhibidores de Proteínas Quinasas / Proteína Serina-Treonina Quinasas de Interacción con Receptores Límite: Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Espiro / Compuestos Aza / Inhibidores de Proteínas Quinasas / Proteína Serina-Treonina Quinasas de Interacción con Receptores Límite: Humans Idioma: En Revista: Bioorg Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido