Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21999, South Korea.
Severance Institute for Vascular and Metabolic Research Yonsei University School of Medicine, Seoul, 06230, South Korea.
Eur J Pharmacol. 2021 May 15;899:174011. doi: 10.1016/j.ejphar.2021.174011. Epub 2021 Mar 9.
Forkhead transcription factor forkhead box O1 (FoxO1) plays an important role in glucose and lipid metabolism, contributing to the pathogenesis of metabolic disorders. This study aimed to discover a novel FoxO1 inhibitor as a potential new anti-diabetic drug candidate, and describes the biological effects of JY-2, 5-(2,4-dichlorophenyl)-3-(pyridin-2-yl)-1,2,4-oxadiazole in vitro and in vivo. JY-2 inhibited FoxO1 transcriptional activity in a concentration-dependent manner, with an IC value of 22 μM. The inhibitory effects of JY-2 on FoxO3a and FoxO4 appeared to be weaker than that on FoxO1. Consistent with its inhibitory effect on FoxO1, JY-2 reduced the palmitic acid (PA)-stimulated mRNA expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes involved in gluconeogenesis in HepG2 cells. In association with the reduced expression of lipid metabolism genes, triglyceride accumulation was also reduced by JY-2, as determined by Oil Red O staining. In addition, JY-2 restored PA-impaired glucose-stimulated insulin secretion (GSIS), in conjunction with an increased mRNA expression of PDX1, MafA, and insulin in INS-1 cells. The in vivo efficacy of JY-2 was examined using C57BL/6J, db/db, and high fat-diet induced obese and diabetic (DIO) mice models, and showed that JY-2 improved glucose tolerance, in parallel with a reduced mRNA expression of gluconeogenic genes. Pharmacokinetic analysis revealed that JY-2 exhibited excellent oral bioavailability (98%), with little adverse effects. These results demonstrated that the novel FoxO1 inhibitor, JY-2, may exert beneficial anti-diabetic effects and that it warrants further investigation as a novel anti-diabetic drug candidate.
叉头框转录因子 O1（FoxO1）在葡萄糖和脂质代谢中发挥重要作用，有助于代谢紊乱的发病机制。本研究旨在发现一种新型 FoxO1 抑制剂作为潜在的新型抗糖尿病药物候选物，并描述了 JY-2，5-（2,4-二氯苯基）-3-（吡啶-2-基）-1,2,4-恶二唑在体外和体内的生物学效应。JY-2 以浓度依赖的方式抑制 FoxO1 转录活性，IC 值为 22 μM。JY-2 对 FoxO3a 和 FoxO4 的抑制作用似乎弱于对 FoxO1 的抑制作用。与抑制 FoxO1 一致，JY-2 降低了棕榈酸（PA）刺激的葡萄糖-6-磷酸酶（G6Pase）和磷酸烯醇丙酮酸羧激酶（PEPCK）mRNA 表达，这两种关键酶参与了 HepG2 细胞中的糖异生。伴随着脂质代谢基因表达的降低，JY-2 还减少了油红 O 染色法测定的甘油三酯积累。此外，JY-2 恢复了 PA 损害的葡萄糖刺激胰岛素分泌（GSIS），同时增加了 INS-1 细胞中 PDX1、MafA 和胰岛素的 mRNA 表达。在 C57BL/6J、db/db 和高脂肪饮食诱导肥胖和糖尿病（DIO）小鼠模型中，对 JY-2 的体内疗效进行了检查，结果表明 JY-2 改善了葡萄糖耐量，同时降低了糖异生基因的 mRNA 表达。药代动力学分析表明，JY-2 具有良好的口服生物利用度（98%），几乎没有不良反应。这些结果表明，新型 FoxO1 抑制剂 JY-2 可能具有有益的抗糖尿病作用，值得进一步研究作为新型抗糖尿病药物候选物。
