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  • Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.

Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.

Cell metabolism (2006-06-07)
Barbara Cool, Bradley Zinker, William Chiou, Lemma Kifle, Ning Cao, Matthew Perham, Robert Dickinson, Andrew Adler, Gerard Gagne, Rajesh Iyengar, Gang Zhao, Kennan Marsh, Philip Kym, Paul Jung, Heidi S Camp, Ernst Frevert
RESUMEN

AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.

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A-769662, ≥98% (HPLC)