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 pyrrolo derivatives as AMPK direct activators. We will illustrate the synthesis and structure-activity relationships of the series as well as some attempts to improve oral bioavailability. Some compounds exhibited very interesting profiles when evaluated orally in different diabetic and obese animal models.

Discovery of oral AMPK direct activators for the treatment of diabetes

243rd National Meeting (2012)

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