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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 5 vom: 09. März, Seite 3566-3587 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Laghezza, Antonio [VerfasserIn] |
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| Links: |
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| Themen: |
Hypoglycemic Agents |
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| Anmerkungen: |
Date Completed 10.03.2023 Date Revised 13.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.2c02093 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM352974893 |
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| 245 | 1 | 2 | |a 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 |
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| 520 | |a 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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| 700 | 1 | |a Cerchia, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Genovese, Massimo |e verfasserin |4 aut | |
| 700 | 1 | |a Leuci, Rosalba |e verfasserin |4 aut | |
| 700 | 1 | |a Pranzini, Erica |e verfasserin |4 aut | |
| 700 | 1 | |a Santi, Alice |e verfasserin |4 aut | |
| 700 | 1 | |a Brunetti, Leonardo |e verfasserin |4 aut | |
| 700 | 1 | |a Piemontese, Luca |e verfasserin |4 aut | |
| 700 | 1 | |a Tortorella, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Biswas, Abanish |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Ravi Pratap |e verfasserin |4 aut | |
| 700 | 1 | |a Tambe, Suhas |e verfasserin |4 aut | |
| 700 | 1 | |a Ca, Sudeep |e verfasserin |4 aut | |
| 700 | 1 | |a Pattnaik, Ashok Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Jayaprakash, Venkatesan |e verfasserin |4 aut | |
| 700 | 1 | |a Paoli, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Lavecchia, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Loiodice, Fulvio |e verfasserin |4 aut | |
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