2. Academic Validation
  3. A New Antidiabetic Agent Showing Short- and Long-Term Effects Due to Peroxisome Proliferator-Activated Receptor Alpha/Gamma Dual Agonism and Mitochondrial Pyruvate Carrier Inhibition

A New Antidiabetic Agent Showing Short- and Long-Term Effects Due to Peroxisome Proliferator-Activated Receptor Alpha/Gamma Dual Agonism and Mitochondrial Pyruvate Carrier Inhibition

  • J Med Chem. 2023 Feb 15. doi: 10.1021/acs.jmedchem.2c02093.
Antonio Laghezza 1,  Carmen Cerchia 2,  Massimo Genovese 3,  Rosalba Leuci 1,  Erica Pranzini 3,  Alice Santi 3,  Leonardo Brunetti 1,  Luca Piemontese 1,  Paolo Tortorella 1,  Abanish Biswas 4,  Ravi Pratap Singh 4,  Suhas Tambe 5,  Sudeep Ca 6,  Ashok Kumar Pattnaik 4,  Venkatesan Jayaprakash 4,  Paolo Paoli 3,  Antonio Lavecchia 2,  Fulvio Loiodice 1
Affiliations

Affiliations

  • 1 Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125 Bari, Italy.
  • 2 Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli "Federico II", via D. Montesano 49, 80131 Napoli, Italy.
  • 3 Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
  • 4 Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
  • 5 Adgyl Lifesciences Private Ltd., Bengaluru 560058, India.
  • 6 Bioanalytical Section, Eurofins Advinus Biopharma Services India Pvt. Ltd., Bengaluru 560058, India.
PMID: 36790935 DOI: 10.1021/acs.jmedchem.2c02093
Abstract

A new series of analogues or derivatives of the previously reported PPARα/γ dual agonist LT175 allowed the identification of ligand 10, which was able to potently activate both PPARα and -γ subtypes as full and partial agonists, respectively. Docking studies were performed to provide a molecular explanation for this different behavior on the two different targets. In vivo experiments showed that this compound induced a significant reduction in blood glucose and lipid levels in an STZ-induced diabetic mouse model displaying no toxic effects on bone, kidney, and liver. By examining in depth the antihyperglycemic activity of 10, we found out that it produced a slight but significant inhibition of the mitochondrial pyruvate carrier, acting also through insulin-independent mechanisms. This is the first example of a PPARα/γ dual agonist reported to show this inhibitory effect representing, therefore, the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.

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