Discovery of a promising agent IQZ23 for the treatment of obesity and related metabolic disorders
Discovery of a promising agent IQZ23 for the treatment of obesity and related metabolic disorders
复制标题
发现一种有前途的药物 IQZ23，用于治疗肥胖和相关代谢紊乱
DOI：
10.1016/j.ejmech.2020.112172
复制
发表时间：
2020
影响因子：
6.7
通讯作者：
Zhi-Shu Huang
中科院分区：
文献类型：
--
作者：
Yong Rao;Zhao Xu;Yu-Tao Hu;Chan Li;Yao-Hao Xu;Qin-Qin Song;Hong Yu;Bing-Bing Song;Shuo-Bin Chen;Qing-Jiang Li;Shi-Liang Huang;Jia-Heng Tan;Tian-Miao Ou;Hong-Gen Wang;Guo-Ping Zhong;Ji-Ming Ye;Zhi-Shu Huang
新型减肥药物的发现是一个具有挑战性和前景的研究领域。本文在前人工作的基础上，通过改变β-吲哚喹唑啉的骨架结构和引入优先侧链，合成了40个新的β-吲哚喹唑啉类似物，评价了它们的降脂活性，并总结了它们的构效关系。通过对化合物23的降血脂作用、AMPK激活能力和肝微粒体稳定性的评价，筛选出化合物23（IQZ 23）作为进一步研究的目标化合物，IQZ 23对3 T3-L1脂肪细胞的甘油三酯水平具有显著的降低作用（EC 50 = 0.033 μM）。机制研究表明IQZ 23的降脂活性依赖于AMPK途径，通过调节ATP合酶活性。这种激活伴随着线粒体生物合成和氧化能力的增加，并通过各种干预措施在相关细胞模型中增强胰岛素敏感性。相应地，IQZ 23（20 mg/kg，i. p.）治疗显著逆转了高脂肪和胆固醇饮食（HFC）诱导的小鼠体重增加和伴随的肥胖临床症状，但没有指示性毒性。这些结果表明IQZ 23可能是治疗肥胖和相关代谢紊乱的有用候选物。
Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novelβ-indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound23(named asIQZ23) was selected for further studies.IQZ23exerted a high efficacy in decreasing the triglyceride level (EC50= 0.033 μM) in 3T3-L1 adipocytes. Mechanistic studies revealed the lipid-lowering activity ofIQZ23was dependent on the AMPK pathway by modulating ATP synthase activity. This activation was accompanied by mitochondrial biogenesis and oxidation capacity increased, and insulin sensitivity enhanced in pertinent cell models by various interventions. Correspondingly,IQZ23(20 mg/kg,i.p.) treatment significantly reversed high fat and cholesterol diet (HFC)- induced body weight increases and accompanying clinical symptoms of obesity in mice but without indicative toxicity. These results indicate thatIQZ23could be a useful candidate for the treatment of obesity and related metabolic disorders.