Novel Phenyldiazenyl Fibrate Analogues as PPAR α/γ/δ Pan-Agonists for the Amelioration of Metabolic Syndrome

Abstract

The development of PPARα/γ dual or PPARα/γ/δ pan-agonists could represent an efficacious approach for a simultaneous pharmacological intervention on carbohydrate and lipid metabolism. Two series of new phenyldiazenyl fibrate derivatives of GL479, a previously reported PPARα/γ dual agonist, were synthesized and tested. Compound 12a was identified as a PPAR pan-agonist with moderate and balanced activity on the three PPAR isoforms (α, γ, δ). Moreover, docking experiments showed that 12a adopts a different binding mode in PPARγ compared to PPARα or PPARδ, providing a structural basis for further structure-guided design of PPAR pan-agonists. The beneficial effects of 12a were evaluated both in vitro, on the expression of PPAR target key metabolic genes, and ex vivo in two rat tissue inflammatory models. The obtained results allow considering this compound as an interesting lead for the development of a new class of PPAR pan-agonists endowed with an activation profile exploitable for therapy of metabolic syndrome.

Lifestyle and Food Habits Impact on Chronic Diseases: Roles of PPARs

“…Recently, more attention is pointed toward the possible use of natural compounds, such as PUFAn3, oleoylethanolamide and β-aminoisobutyric acid, natural and endogenous ligands of PPARs. Finally, the development of PPARα/γ/δ pan-agonists or PPARα/γ dual agonist [314] could be a potential therapy for a concomitant pharmacological activity on carbohydrate and lipid metabolism.…”

Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study

“…Conversely, none of the compounds had activity over PPARα expression, whereas clofibrate did. This implies that azasubstituents (nitro and acetamide), instead of the chlorine atom in the phenyl ring, provoke a selectivity of compounds over PPARγ instead PPARα and are able to behave as selective PPAR modulators (SPPARM) [10].…”

Design, Synthesis and Biological Evaluation of Aromatase Inhibitors Based on Sulfonates and Sulfonamides of Resveratrol

“…In the past few years, we focused on the synthesis of various series of RSV derivatives. Among them, stilbene hybrids of fibrates showed very interesting activity on many different targets such as the Peroxisome Proliferator-Activated Receptors (PPARs) [44][45][46][47][48]. To enlarge the biological potential of RSV derivatives, and to ameliorate the pharmacokinetic profile, the hydroxy groups in the 3 and 5 positions were substituted with hydrogens and different functional groups were inserted in the 4'-position.…”