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

Abstract

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.

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…Moreover, increased cGMP levels can enhance AMP kinase (AMPK) activity 38 , which in turn may act on the clock by promoting CRY-protein degradation 39 . Activation of AMPK in the liver also represses expression of gluconeogenesis enzymes such as Pck1 and G6pc 40 , results opposite from those observed in heme oxygenase-depleted hepatocytes. If the increases in Pck1 and G6pc transcript levels in HO-depleted hepatocytes were due to decreased AMPK activity (perhaps mediated by increased oxidative stress 41 ), transcript levels of genes involved in other anabolic pathways would also be expected to be elevated 42 .…”

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

“…A prototype of such a drug is the compound A-769662, developed by Abbott laboratories by screening for AMPK activators. In animal models of the metabolic syndrome such as the ob/ob mouse, this compound had many of the effects expected for an AMPK activator, such as lowering blood glucose and triglycerides, lowering liver triglycerides, down-regulating gluconeogenic genes, and even reducing weight gain [86]. Unfortunately, the oral availability of this compound was poor and it was administered to the animals by injection, but it may nevertheless indicate the way forward.…”

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators

“…Several metabolic stress (hypoxia, energy starvation) and certain external factors or drugs, such as AICAR (5-Aminoimidazole-4-carboxamide riboside), phenformin (ATP mitochondrial sintase inhibitor) or metformin (antihyperglycemic agent used in the treatment of diabetes), are able to activate AMPK in vitro and in vivo. Recently, a novel small molecule has been proposed as a specific AMPK activator: A-769662 [18]. A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on Thr-172, similar to the effects of AMP [19,20].…”