Chemical Works of Gedeon Richter Plc, 30-32 Gyömrői Street, Budapest H-1103, Hungary; Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3., H-1111 Budapest, Hungary.
Chemical Works of Gedeon Richter Plc, 30-32 Gyömrői Street, Budapest H-1103, Hungary.
Bioorg Med Chem Lett. 2024 Nov 15;113:129970. doi: 10.1016/j.bmcl.2024.129970. Epub 2024 Sep 19.
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors. Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and in vivo hypothermia study in mice.
受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIPK1）在细胞死亡和炎症中起着至关重要的作用。开发新型 RIPK1 介导的坏死性凋亡抑制剂的一种很有前途的方法是将已知的 RIPK1 抑制剂的不同结合模式混合到一个分子中。在此，我们报告了新型混合类型抑制剂的合成和生物学评价。以 Eclitasertib 为起点，并应用我们之前关于环丙二酰胺的已发表知识，我们成功地鉴定了一系列活性化合物。最平衡和最有前途的化合物的活性对映体进行了药代动力学和体内降温研究。
