2. Academic Validation
  3. Novel Phenyldiazenyl Fibrate Analogues as PPAR α/γ/δ Pan-Agonists for the Amelioration of Metabolic Syndrome

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

  • ACS Med Chem Lett. 2019 Feb 25;10(4):545-551. doi: 10.1021/acsmedchemlett.8b00574.
Letizia Giampietro 1,  Antonio Laghezza 2,  Carmen Cerchia 3,  Rosalba Florio 1 4,  Lucia Recinella 1,  Fabio Capone 3,  Alessandra Ammazzalorso 1,  Isabella Bruno 1,  Barbara De Filippis 1,  Marialuigia Fantacuzzi 1,  Claudio Ferrante 1,  Cristina Maccallini 1,  Paolo Tortorella 2,  Fabio Verginelli 1 4,  Luigi Brunetti 1,  Alessandro Cama 1 4,  Rosa Amoroso 1,  Fulvio Loiodice 2,  Antonio Lavecchia 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Chieti "G. d.Annunzio", Via Dei Vestini, 31, 66100 Chieti, Italy.
  • 2 Department of Pharmacy-Drug Science, University of Bari "Aldo Moro", Via E. Orabona, 4, 70126 Bari, Italy.
  • 3 Department of Pharmacy, "Drug Discovery" Laboratory, University of Napoli "Federico II", Via D. Montesano, 49, 80131 Napoli, Italy.
  • 4 Center of Aging Science and Translational Medicine (CeSI-MeT), University of Chieti "G. d'Annunzio", Via Luigi Polacchi 11, 66100 Chieti, Italy.
PMID: 30996794 DOI: 10.1021/acsmedchemlett.8b00574
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.

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