设计和合成 AMPK 激活剂和 GDF15 诱导剂。
Design and Synthesis of AMPK Activators and GDF15 Inducers.
机构信息
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain.
出版信息
Molecules. 2023 Jul 17;28(14):5468. doi: 10.3390/molecules28145468.
Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, . This molecule showed a better potency than metformin, increasing mRNA levels in human Huh-7 hepatic cells. Based on , structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound showed a higher increase in mRNA levels compared with . Metformin, , and compound increased phosphorylated AMPK, but only increased GDF15 protein levels. Overall, these findings indicate that has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and .
靶向生长分化因子 15（GDF15）是治疗肥胖症和 2 型糖尿病（T2DM）的新策略。在这里，我们设计、合成并在体外对一系列新型 AMPK 激活剂进行了药理学评价，以上调 GDF15 水平。这些化合物基于孤儿泛素 E3 连接酶亚基蛋白 Fbxo48 抑制剂的（1-二苄基氨基-3-苯氧基）丙-2-醇结构， 。与二甲双胍相比，该分子具有更好的效力，可增加人 Huh-7 肝细胞中的 mRNA 水平。基于 ，进行了结构修饰以创建一系列具有不同取代基的新分子。在所评估的 35 种新化合物中，化合物 与 相比， mRNA 水平升高幅度更高。与二甲双胍、 和化合物 相比，可增加磷酸化 AMPK，但只有 可增加 GDF15 蛋白水平。总的来说，这些发现表明与二甲双胍和 相比， 具有独特的能力可增加人肝细胞中的 GDF15 蛋白水平。
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