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 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.
Authors
- Aurélien Thomas (ORCID: https://orcid.org/0000-0001-6790-2285)
- Paolo Tortorella (ORCID: https://orcid.org/0000-0003-1358-7376)
- Emanuele Falbo (ORCID: https://orcid.org/0000-0002-7658-1724)
- Paolo Paoli (ORCID: https://orcid.org/0000-0001-6448-7266)
- Sudeep Ca (ORCID: https://orcid.org/0000-0002-2995-3986)
- Ashok Pattnaik
- Suhas Tambe (ORCID: https://orcid.org/0000-0002-1695-8198)
- Ravi Pratap Singh (ORCID: https://orcid.org/0000-0002-2077-9619)
- Luca Piemontese (ORCID: https://orcid.org/0000-0002-7980-5818)
- Antonio Laghezza (ORCID: https://orcid.org/0000-0001-6221-6155)
- Rosalba Leuci (ORCID: https://orcid.org/0000-0002-5229-988X)
- Federica Gilardi (ORCID: https://orcid.org/0000-0001-5421-2779)
- Fulvio Loiodice (ORCID: https://orcid.org/0000-0003-3384-574X)
- Venkatesan Jayaprakash (ORCID: https://orcid.org/0000-0002-9724-4153)
- Abanish Biswas (ORCID: https://orcid.org/0000-0002-4871-0453)
- Antonio Lavecchia (ORCID: https://orcid.org/0000-0002-2181-8026)
- Leonardo Brunetti (ORCID: https://orcid.org/0000-0002-7787-6639)
- Judith Wackerlig-Damle
Institutions
- Birla Institute of Technology, Mesra (IN)
- University of Vienna (AT)
- Bioanalytica (Switzerland) (CH)
- Federico II University Hospital (IT)
- TCG Lifesciences (India) (IN)
- University Centre of Legal Medicine (CH)
- Olive Lifesciences (India) (IN)
- University of Florence (IT)
- University of Bari Aldo Moro (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- European Journal of Medicinal Chemistry
- Published
- 2025-03-11
- DOI
- https://doi.org/10.1016/j.ejmech.2025.117494
- Citations
- 2
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Università degli Studi di Napoli Federico II
- European Commission
- Universität Wien