Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175

Piemontese, Luca; Fracchiolla, Giuseppe; Carrieri, Antonio; Parente, Mariagiovanna; Laghezza, Antonio; Carbonara, Giuseppe; Sblano, Sabina; Tauro, Marilena; Gilardi, Federica; Tortorella, Paolo; Lavecchia, Antonio; Crestani, Maurizio; Desvergne, Béatrice; Loiodice, Fulvio

doi:10.1016/j.ejmech.2014.11.044

Cited by 24 publications

(17 citation statements)

References 44 publications

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“…PPARγ ligands have shown great promise for therapeutic interventions in metabolic disorders such as T2DM. However, in spite of being effective in normalization of blood glucose levels, so far experienced unwanted side effects of the currently used PPARγ agonists from TDZs, promote the search for new PPARγactivators [ 5 , 9 , 35 ]. Reportedly it was found that PPARγ could induce FGF21 which in turn amplified PPARγ activity and promoted insulin sensitization, whereas blockage of FGF21 could lead to decrease the insulin- sensitizing effects of TDZs as well as increasing the associated weight gain and fluid retention, implicating FGF21 as a vital mediator of the anti-diabetic actions and negative side effects of TDZs [ 5 , 23 – 25 ].…”

Section: Discussionmentioning

confidence: 99%

Ampelopsin Improves Insulin Resistance by Activating PPARγ and Subsequently Up-Regulating FGF21-AMPK Signaling Pathway

Zhou

Qin

et al. 2016

PLoS ONE

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Ampelopsin (APL), a major bioactive constituent of Ampelopsis grossedentata, exerts a number of biological effects. Here, we explored the anti-diabetic activity of APL and elucidate the underlying mechanism of this action. In palmitate-induced insulin resistance of L6 myotubes, APL treatment markedly up- regulated phosphorylated insulin receptor substrate-1 and protein kinase B, along with a corresponding increase of glucose uptake capacity. APL treatment also increased expressions of fibroblast growth factor (FGF21) and phosphorylated adenosine 5’-monophosphate -activated protein kinase (p-AMPK), however inhibiting AMPK by Compound C or AMPK siRNA, or blockage of FGF21 by FGF21 siRNA, obviously weakened APL -induced increases of FGF21 and p-AMPK as well as glucose uptake capacity in palmitate -pretreated L6 myotubes. Furthermore, APL could activate PPAR γ resulting in increases of glucose uptake capacity and expressions of FGF21 and p-AMPK in palmitate -pretreated L6 myotubes, whereas all those effects were obviously abolished by addition of GW9662, a specific inhibitor of peroxisome proliferator- activated receptor –γ (PPARγ), and PPARγsiRNA. Using molecular modeling and the luciferase reporter assays, we observed that APL could dock with the catalytic domain of PPARγ and dose-dependently up-regulate PPARγ activity. In summary, APL maybe a potential agonist of PPARγ and promotes insulin sensitization by activating PPARγ and subsequently regulating FGF21- AMPK signaling pathway. These results provide new insights into the protective health effects of APL, especially for the treatment of Type 2 diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Ampelopsin Improves Insulin Resistance by Activating PPARγ and Subsequently Up-Regulating FGF21-AMPK Signaling Pathway

Zhou

Qin

et al. 2016

PLoS ONE

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“…55 Yet, newer dual PPAR α/γ agonists are being developed. [56][57][58] Figure 6. The effects of PPAR γ and PPAR α silencing on the protective effect of Ale on cell viability in cardiomyocytes exposed to HG.…”

Section: Discussionmentioning

confidence: 99%

Aleglitazar, a dual peroxisome proliferator-activated receptor-α and -γ agonist, protects cardiomyocytes against the adverse effects of hyperglycaemia

Chen

Birnbaum

et al. 2017

Diabetes and Vascular Disease Research

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Purpose:To assess the effects of Aleglitazar on hyperglycaemia-induced apoptosis.Methods:We incubated human cardiomyocytes, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout or wild-type mice in normoglycaemic or hyperglycaemic conditions (glucose 25 mM). Cells were treated with different concentrations of Aleglitazar for 48 h. We measured viability, apoptosis, caspase-3 activity, cytochrome-C release, total antioxidant capacity and reactive oxygen species formation in the treated cardiomyocytes. Human cardiomyocytes were transfected with short interfering RNA against peroxisome proliferator-activated receptor-α or peroxisome proliferator-activated receptor-γ.Results:Aleglitazar attenuated hyperglycaemia-induced apoptosis, caspase-3 activity and cytochrome-C release and increased viability in human cardiomyocyte, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout and wild-type mice. Hyperglycaemia reduced the antioxidant capacity and Aleglitazar significantly blunted this effect. Hyperglycaemia-induced reactive oxygen species production was attenuated by Aleglitazar in both human cardiomyocyte and wild-type mice cardiomyocytes. Aleglitazar improved cell viability in cells exposed to hyperglycaemia. The protective effect was partially blocked by short interfering RNA against peroxisome proliferator-activated receptor-α alone and short interfering RNA against peroxisome proliferator-activated receptor-γ alone and completely blocked by short interfering RNA to both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ.Conclusion:Aleglitazar protects cardiomyocytes against hyperglycaemia-induced apoptosis by combined activation of both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ in a short-term vitro model.

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“…In vein of this issue and starting from our ongoing project on binders acting as Peroxisome Proliferator‐Activated Receptors (PPARs) agonists, we recovered some oxime derivatives previously obtained from the lead compound LT175 . This series of PPARs ligands was designed according to indications furnished in a previous work validating the bioisosteric replacement of a phenyl ring with oxime function.…”

Section: Methodsmentioning

confidence: 99%

Repositioning of Endonuclear Receptors Binders as Potential Antibacterial and Antifungal Agents. Eptyloxìm: A Potential and Novel Gyrase B and Cytochrome Cyp51 Inhibitor

Carrieri

L'Abbate

Chicco

et al. 2016

Molecular Informatics

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Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175

Cited by 24 publications

References 44 publications

Ampelopsin Improves Insulin Resistance by Activating PPARγ and Subsequently Up-Regulating FGF21-AMPK Signaling Pathway

Ampelopsin Improves Insulin Resistance by Activating PPARγ and Subsequently Up-Regulating FGF21-AMPK Signaling Pathway

Aleglitazar, a dual peroxisome proliferator-activated receptor-α and -γ agonist, protects cardiomyocytes against the adverse effects of hyperglycaemia

Repositioning of Endonuclear Receptors Binders as Potential Antibacterial and Antifungal Agents. Eptyloxìm: A Potential and Novel Gyrase B and Cytochrome Cyp51 Inhibitor

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