Abstract
Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone. Another 12 tetrazoles based on the bioisosterism principle were obtained accordingly. Furthermore, in vitro PPARs transactivation assays on these 3- or 4-alkoxy substituted phenoxy derivatives afforded six compounds. Interactions and binding stability from the docking analysis and 20 ns molecular dynamic simulations confirmed the representative compounds to be suitable and plausible for PPARs pockets. The above-mentioned results demonstrated that the compounds may be used as reference for further optimization for enhanced PPARs activities and wide safety range.
Highlights
Peroxisome proliferators-activated receptors (PPARα, γ and δ) are classified as ligand-inducible nuclear receptors [1, 2]
PPARγ ligands glitazones are deemed as insulin sensitizer to improve the symptoms of patients with Type 2 diabetes mellitus (T2DM) [9]
The general synthetic routes of carboxylic acids and tetrazole compounds were depicted in Schemes 1 and 2, respectively
Summary
Peroxisome proliferators-activated receptors (PPARα, γ and δ) are classified as ligand-inducible nuclear receptors [1, 2]. They were attractive targets for diabetes, dyslipidemia, obesity, inflammation and atherosclerosis [3]. Fatty acid oxidation and lipoprotein metabolism would be improved. PPARγ which highly ameliorates insulin sensitivity is widely expressed in adipose tissues [6,7,8]. PPARγ ligands glitazones (rosiglitazone and pioglitazone, Figure 1) are deemed as insulin sensitizer to improve the symptoms of patients with Type 2 diabetes mellitus (T2DM) [9]. GW501516 which exhibited potent and selective PPARδ agonism has previously entered clinical trials [12]
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