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Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy.
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2019-11-19 , DOI: 10.1080/14756366.2019.1690481
Lingling Yang 1 , Feng Chen 1 , Cheng Gao 1 , Jiabao Chen 1 , Junyan Li 1 , Siyan Liu 1 , Yuanyuan Zhang 2 , Zhouyu Wang 2 , Shan Qian 1
Affiliation  

Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide-streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.

中文翻译:

三环萜类衍生物作为新型PTP1B抑制剂的设计和合成,具有改进的药理特性和体内抗高血糖功效。

在各种基础和临床研究中,蛋白酪氨酸磷酸酶1B(PTP1B)的过表达诱导胰岛素抵抗。在我们以前的工作中,已经报道了具有PTP1B抑制活性的合成齐墩果酸(OA)衍生物C10a。但是,C10a具有一些药理缺陷和细胞毒性。在本文中,基于C10a的结构使用了基于结构的药物设计方法来完善较小的三环核心。合成了一系列三环衍生物,化合物15、28和34表现出最大的PTP1B酶促抑制能力。在具有胰岛素抵抗性的人肝癌HepG2细胞中,具有中等PTP1B抑制作用和较好药物特性的化合物25可以显着增加胰岛素刺激的葡萄糖摄取,并显示出改善胰岛素抵抗的作用。而且,图25显示了在烟酰胺-链脲佐菌素诱导的T2D中改善的体内抗高血糖潜能。我们的研究表明,这些具有改善的分子结构和抗高血糖活性的三环衍生物可用于治疗T2D。
更新日期:2020-04-20
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