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

Mar 26, 2017Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

New drugs that activate two targets to improve diabetes: design, creation, and combined testing

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Abstract

Compound 1 demonstrated a 7-times increase in the mRNA expression of PPARγ compared to control.

Compound 1 enhanced GLUT4 expression alongside the increase in PPARγ.
A 2-fold increase in intracellular calcium levels was observed with Compound 1, leading to greater insulin release.
Compound 1's activity matched that of the positive control, glibenclamide, and also increased GPR40 mRNA expression by 2-fold.
Compound 2 exhibited lower biological activity than Compound 1.
Antidiabetic activity of Compound 1 was confirmed at a dosage of 50 mg/kg in a diabetic mouse model.
Molecular docking studies indicate strong binding affinity of Compound 1 to both PPARγ and GPR40 receptors.

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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 [Ca] 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 [Ca]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. 2+ 2+ i

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

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