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.

中文翻译：

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6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑衍生物作为坏死性凋亡抑制剂的设计、合成及构效关系研究


坏死性凋亡抑制剂的开发已成为有效减轻坏死性凋亡相关炎症性疾病、神经退行性疾病和癌症的有效策略。在本文中，我们报道了一系列作为有效的坏死性凋亡抑制剂的6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑衍生物。代表性化合物 26 在人和小鼠细胞测定中均表现出有效的抗坏死性凋亡活性，并且对受体相互作用蛋白激酶 1 (RIPK1) 表现出有效的抑制活性。进行体内药代动力学研究以确定化合物26的口服暴露量。最后，分子对接阐明化合物26可以有效结合RIPK1的变构袋并充当III型抑制剂。总而言之，我们的研究结果强调，化合物 26 代表了未来坏死性凋亡抑制剂开发的一种有前景的先导化合物。