Discovery of Pyridones As Oral AMPK Direct Activators

作者：Mirguet Olivier^*; Sautet Stephane; Clement Catherine Anne; Toum Jerome; Donche Frederic; Marques Celine; Rondet Emilie; Pizzonero Mathieu; Beaufils Benjamin; Dudit Yann; Huet Pascal; Trottet Lionel; Grondin Pascal; Brusq Jean Marie; Boursier Eric; Saintillan Yannick; Nicodeme Edwige

来源：ACS Medicinal Chemistry Letters, 2013, 4(7): 67-71.

DOI：10.1021/ml400157g

• AMPK direct activator
• pyridone
• P-gp substrate
• type 2 diabetes

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.

• 出版日期2013-7