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

• Published in: Journal of medicinal chemistry Vol. 66; no. 5; pp. 3566 - 3587
• Main Authors: Laghezza, Antonio, Cerchia, Carmen, Genovese, Massimo, Leuci, Rosalba, Pranzini, Erica, Santi, Alice, Brunetti, Leonardo, Piemontese, Luca, Tortorella, Paolo, Biswas, Abanish, Singh, Ravi Pratap, Tambe, Suhas, CA, Sudeep, Pattnaik, Ashok Kumar, Jayaprakash, Venkatesan, Paoli, Paolo, Lavecchia, Antonio, Loiodice, Fulvio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.03.2023; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Diabetes Mellitus, Type 2 - drug therapy; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Life Sciences & Biomedicine; Mice; Monocarboxylic Acid Transporters; Pharmacology & Pharmacy; PPAR alpha - metabolism; PPAR gamma - metabolism; PPAR-gamma Agonists; Science & Technology; CONDUCTANCE; SKELETAL-MUSCLE; PPAR; ALPHA; RISK; FLUORINE; PHYSIOLOGICAL FUNCTIONS; MODULATOR; THIAZOLIDINEDIONES; CARBOXYLIC-ACIDS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c02093

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.