Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Ligand Choreography: Newcomers Take the Stage

Journal of Medicinal Chemistry
Santiago Garcia-VallvéMiquel Mulero

Abstract

Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) full agonists that have been widely used in the treatment of type 2 diabetes mellitus. Despite the demonstrated beneficial effect of reducing glucose levels in the plasma, TZDs also induce several adverse effects. Consequently, the search for new compounds with potent antidiabetic effects but fewer undesired effects is an active field of research. Interestingly, the novel proposed mechanisms for the antidiabetic activity of PPARγ agonists, consisting of PPARγ Ser273 phosphorylation inhibition, ligand and receptor mutual dynamics, and the presence of an alternate binding site, have recently changed the view regarding the optimal characteristics for the screening of novel PPARγ ligands. Furthermore, transcriptional genomics could bring essential information about the genome-wide effects of PPARγ ligands. Consequently, facing the new mechanistic scenario proposed for these compounds is essential for resolving the paradoxes among their agonistic function, antidiabetic activities, and side effects and should allow the rational development of better and safer PPARγ-mediated antidiabetic drugs.

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Citations

Mar 31, 2016·Assay and Drug Development Technologies·Nina ProkophJianming Liu
Dec 28, 2016·International Journal of Molecular Sciences·Melina MottinMunir S Skaf
Feb 18, 2017·International Journal of Molecular Sciences·Maria PetrosinoRoberta Chiaraluce
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Dec 17, 2019·Journal of Biomolecular Structure & Dynamics·Meenakshi DuhanParvin Kumar
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Jan 24, 2019·Journal of Natural Products·Sungjin AhnMinsoo Noh

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