Discovery of new dual PPAR gamma-GPR40 agonists with robust antidiabetic activity: Design, synthesis and in combo drug evaluation

作者：Hidalgo Figueroa Sergio^*; Navarrete Vazquez Gabriel; Estrada Soto Samuel; Giles Rivas Diana; Alarcon Aguilar Francisco J; Leon Rivera Ismael; Giacoman Martinez Abraham; Miranda Perez Elizabeth; Almanza Perez Julio C^*

来源：Biomedicine & Pharmacotherapy, 2017, 90: 53-61.

DOI：10.1016/j.biopha.2017.03.033

• PPAR gamma
• GPR40
• Dual agonist
• Insulin secretion
• Antidiabetic action
• Molecular docking

The design of compounds 1 and 2 was based on the similar scaffold of pharmacophoric groups for PPAR gamma and GPR40 agonists. In order to find new compounds with improved biological activity, the current manuscript describes a new dual PPAR gamma-GPR40 agonist. We synthesized two compounds, which were prepared following a multistep synthetic route, and the relative mRNA expression levels of PPAR gamma, GLUT4, and GPR40 were quantified in cell culture, as well as insulin secretion and [Ca2+] intracellular levels. Compound 1 showed a 7-times increase in the mRNA expression of PPAR gamma, which in turn enhanced the expression levels of GLUT4 respect to control and pioglitazone. It also showed an increase of 2-fold in the [Ca2+](i) level allowing an increment on insulin release, being as active as the positive control (glibenclamide), causing also an increase of 2-fold in mRNA expression of GPR40. Furthermore, the compound 2 showed lower activity than the compound 1. The ester of 1 showed antidiabetic activity at a 50 mg/kg single dose in streptozotocin-nicotinamide-induced diabetic mice model. In addition, we achieved a molecular docking study of compound 1 on PPAR gamma and GPR40 receptors, showing a great affinity for both targets. We observed important polar interactions between the carboxylic group and main residues into the binding pocket. Therefore, the compound 1 has a potential for the development of antidiabetic agents with newfangled dual action.

• 出版日期2017-6