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  3. A new potent and selective peroxisome proliferator-activated receptor alpha partial agonist displays anti-steatotic effects In vitro and behaves as a safe hypolipidemic and hypoglycemic agent in a diabetic mouse model

A new potent and selective peroxisome proliferator-activated receptor alpha partial agonist displays anti-steatotic effects In vitro and behaves as a safe hypolipidemic and hypoglycemic agent in a diabetic mouse model

  • Eur J Med Chem. 2025 May 5:289:117494. doi: 10.1016/j.ejmech.2025.117494.
Antonio Laghezza 1,  Emanuele Falbo 2,  Federica Gilardi 3,  Aurélien Thomas 3,  Leonardo Brunetti 1,  Rosalba Leuci 1,  Luca Piemontese 1,  Paolo Tortorella 1,  Abanish Biswas 4,  Ravi Pratap Singh 4,  Ashok Kumar Pattnaik 4,  Venkatesan Jayaprakash 4,  Suhas Tambe 5,  Sudeep Ca 6,  Judith Wackerlig-Damle 7,  Paolo Paoli 8,  Fulvio Loiodice 9,  Antonio Lavecchia 10
Affiliations

Affiliations

  • 1 Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro, 70125, Bari, Italy.
  • 2 Department of Pharmacy, "Drug Discovery" Laboratory, University of Napoli Federico II, 80131, Napoli, Italy.
  • 3 Faculty Unit of Toxicology, CURML, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; Unit of Forensic Toxicology and Chemistry, CURML, Lausanne and Geneva University Hospitals, Lausanne-Geneva, Switzerland.
  • 4 Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India.
  • 5 Adgyl Lifesciences Private Ltd, Bengaluru, Karnataka, 560058, India.
  • 6 Bioanalytical Section, Eurofins Advinus Biopharma Services India Pvt Ltd., Bengaluru, Karnataka, 560058, India.
  • 7 Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090, Vienna, Austria.
  • 8 Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, Università degli Studi di Firenze, viale Morgagni 50, 50134, Firenze, Italy.
  • 9 Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro, 70125, Bari, Italy. Electronic address: fulvio.loiodice@uniba.it.
  • 10 Department of Pharmacy, "Drug Discovery" Laboratory, University of Napoli Federico II, 80131, Napoli, Italy. Electronic address: antonio.lavecchia@unina.it.
PMID: 40088662 DOI: 10.1016/j.ejmech.2025.117494
Abstract

A rational drug design approach led to the synthesis of three pairs of enantiomers derived from the Peroxisome Proliferator-activated Receptor (PPAR) pan agonist AL29-26, identifying (S)-2 as a potent and selective PPARα partial agonist. Molecular docking and molecular dynamics simulations elucidated the binding modes of (S)-2 within the ligand-binding domains of PPARα and PPARγ. In vitro, (S)-2 demonstrated significant anti-steatotic effects, upregulating key PPARα target genes involved in lipid metabolism. In vivo, (S)-2 exhibited hypolipidemic and antihyperglycemic activity in a diabetic mouse model, outperforming fenofibrate in lowering blood glucose and lipid levels, while showing no toxicity in major organs (artery, kidney, liver, pancreas). The therapeutic effects of ((S)-2 were attributed to its PPARα selectivity, reduced activation of PPARγ, and mild protein tyrosine Phosphatase 1B (PTP1B) inhibition. These findings highlight (S)-2 as a promising lead compound for the development of safer and more effective treatments for dyslipidemic type 2 diabetes.

Keywords

Anti-steatotic effects; Docking; Hypolipidemic and hypoglycemic activity; MD simulation; PPARalpha agonist; Stereoselectivity.

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