Abstract
Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 1–4, but an absence of in vitro expression of PPARα was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPARγ. In vivo studies established that compounds 1–4 have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound 2 was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPARγ modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound 2 showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate.
Highlights
Phenoxyisobutyric acid derivatives are a class of antihyperlipidemic agents, commonly known as fibrates, that act mainly as peroxisome proliferator-activated receptor (PPAR)
PPARγ controls target genes involved in numerous biochemical pathways, such as the glucose transporter GLUT-4 [3]
Clofibrate, the first therapeutically useful fibrate, is an ethyl chlorophenoxyisobutyrate that acts as a prodrug, which is metabolized in vivo by esterases into its active metabolite, clofibric acid, that has shown strong hypolipidemic effect [4]
Summary
Phenoxyisobutyric acid derivatives are a class of antihyperlipidemic agents, commonly known as fibrates, that act mainly as peroxisome proliferator-activated receptor (PPAR)modulators [1]. PPARα and PPARγ are the protein targets of several endogenous fatty acids, which function as antidyslipidemic and insulin-sensitizing molecules [2]. Recent studies showed that clofibrate and clofibric acid exerted a potent inhibitory activity against the enzyme 11β-hydroxysteroid dehydrogenase type 1 [5]. This enzyme catalyzes the conversion of inactive cortisone into the active hormone cortisol, a powerful glucocorticoid that acts as a contender of insulin action and stimulates gluconeogenesis in liver, leading to an increase in blood glucose levels and causing hyperglycemia [6]
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