Discovery of Pyridones As Oral AMPK Direct Activators
| Autor: | Jean-Marie Brusq, Pascal Grondin, Benjamin Beaufils, Frédéric Donche, Stéphane Sautet, Celine Marques, Edwige Nicodeme, Yann Dudit, Catherine-Anne Clément, Pascal Huet, Yannick Saintillan, Eric Boursier, Jérôme Toum, Mathieu Pizzonero, Emilie Rondet, Lionel Trottet, Olivier Mirguet |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
chemistry.chemical_classification
medicine.medical_specialty business.industry Organic Chemistry AMPK Type 2 diabetes medicine.disease Biochemistry Proinflammatory cytokine Endocrinology Enzyme Pharmacokinetics chemistry Internal medicine Drug Discovery Hyperlipidemia medicine business Protein kinase A Beta oxidation |
| Popis: | AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for type 2 diabetes and other metabolic disorders. Here, we will report the discovery of pyrrolopyridone derivatives as AMPK direct activators. We will illustrate the synthesis and structure–activity relationships of the series as well as some pharmacokinetic results. Some compounds exhibited encouraging oral exposure and were evaluated in a mouse diabetic model. Compound 17 showed oral activity at 30 mg/kg on blood glucose. |
| Databáze: | OpenAIRE |
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