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
  • 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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