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

Abstract

The design of compounds 1 and 2 was based on the similar scaffold of pharmacophoric groups for PPARγ and GPR40 agonists. In order to find new compounds with improved biological activity, the current manuscript describes a new dual PPARγ-GPR40 agonist. We synthesized two compounds, which were prepared following a multistep synthetic route, and the relative mRNA expression levels of PPARγ, 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 PPARγ, 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 50mg/kg single dose in streptozotocin-nicotinamide-induced diabetic mice model. In addition, we achieved a molecular docking study of compound 1 on PPARγ 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.

Keywords: Antidiabetic action; Dual agonist; GPR40; Insulin secretion; Molecular docking; PPARγ.