Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy

Abstract

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.

Graphical Abstract

Keywords:

• Protein tyrosine phosphatase 1B
• oleanolic acid
• insulin-resistant
• antihyperglycaemic effect
• type 2 diabetes

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The project was sponsored by grants from the National Natural Science Foundation for the Youth of China (81302647), Chengdu Technology Innovation Research Project (2018-YFYF-00195-SN), Sichuan Science and Technology Innovation Seedling Project (2018082), Science and Technology Department of Sichuan Province (2016HH0075), the Found of Sichuan Education Department (18TD0023), Open Project of School of Health Management of Xihua University (SZJJ2017-038), and the Innovation Fund of Xihua Scholars, Undergraduate and Post Graduate from Xihua University.