An Yuxiang, Peng Xia, Wang Tianchen, Liu Kaiyuan, Feng Dazhi, Fang Chen, Zhou Xuan, Geng Meiyu, Duan Wenhu, Ai Jing, Zhang Hefeng
Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China.
Arch Pharm (Weinheim). 2025 Jan;358(1):e2400594. doi: 10.1002/ardp.202400594. Epub 2024 Nov 21.
Necroptosis is a regulated inflammatory cell death process that is closely associated with autoimmune diseases, acute ischemic injuries, neurodegenerative disorders, and so on. Due to the crucial role of receptor-interacting protein kinase 1 (RIPK1) in the necroptosis pathway, RIPK1 inhibitors are believed to have great potential in the treatment of necroptosis-related diseases. In this article, we reported a series of pyridazin-4-one derivatives as potent necroptosis inhibitors for both human and mouse cells. The representative compound 13 exhibited favorable RIPK1 selectivity and dose-dependently inhibited RIPK1 phosphorylation. The in vivo pharmacokinetic study indicated that compound 13 was an orally available candidate. Finally, molecular docking and molecular dynamics simulations were performed to elucidate the binding pattern of compound 13 with RIPK1. Collectively, compound 13 represents a promising lead compound for the future development of RIPK1-targeted necroptosis inhibitors.
坏死性凋亡是一种受调控的炎症性细胞死亡过程，与自身免疫性疾病、急性缺血性损伤、神经退行性疾病等密切相关。由于受体相互作用蛋白激酶1（RIPK1）在坏死性凋亡途径中的关键作用，RIPK1抑制剂被认为在治疗坏死性凋亡相关疾病方面具有巨大潜力。在本文中，我们报道了一系列哒嗪-4-酮衍生物作为人和小鼠细胞的有效坏死性凋亡抑制剂。代表性化合物13表现出良好的RIPK1选择性，并剂量依赖性地抑制RIPK1磷酸化。体内药代动力学研究表明化合物13是一个口服可用的候选物。最后，进行了分子对接和分子动力学模拟以阐明化合物13与RIPK1的结合模式。总体而言，化合物13是RIPK1靶向坏死性凋亡抑制剂未来开发的一个有前景的先导化合物。
