Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.
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.
Cool
Barbara
B
Department of Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. barbara.l.cool@abbott.com
Zinker
Bradley
B
Chiou
William
W
Kifle
Lemma
L
Cao
Ning
N
Perham
Matthew
M
Dickinson
Robert
R
Adler
Andrew
A
Gagne
Gerard
G
Iyengar
Rajesh
R
Zhao
Gang
G
Marsh
Kennan
K
Kym
Philip
P
Jung
Paul
P
Camp
Heidi S
HS
Frevert
Ernst
E
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001713:Biphenyl Compounds; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D020536:Enzyme Activators / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D064429:Fatty Acid Synthases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism; D008687:Metformin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008820:Mice, Obese; D008970:Molecular Weight; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011753:Pyrones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
D001713:Biphenyl Compounds; D020536:Enzyme Activators; D009097:Multienzyme Complexes; D011753:Pyrones; D012333:RNA, Messenger; D013876:Thiophenes; D008687:Metformin; D064429:Fatty Acid Synthases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile