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

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

  • RSC Med Chem. 2024 Jun 21;15(7):2514-2526. doi: 10.1039/d4md00265b.
Zechen Jin 1 2,  Yang Dai 3 2,  Yinchun Ji 3,  Xia Peng 3,  Wenhu Duan 1 2 4,  Jing Ai 3 2,  Hefeng Zhang 1
Affiliations

Affiliations

  • 1 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences 555 Zu Chong Zhi Road Shanghai 201203 China zhanghefeng1@simm.ac.cn.
  • 2 School of Pharmacy, University of Chinese Academy of Sciences No. 19A Yuquan Road Beijing 100049 China.
  • 3 Cancer Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences 555 Zu Chong Zhi Road Shanghai 201203 China jai@simm.ac.cn.
  • 4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery Yantai Shandong 264117 China.
PMID: 39026642 DOI: 10.1039/d4md00265b
Abstract

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-5H-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.

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