Antidiabetic and antiobesity effects of Ampkinone (6f), a novel small molecule activator of AMP-activated protein kinase.
Adenosine 5'-monophosphate (AMP) activated protein kinase (AMPK) has emerged as an attractive target molecule for the treatment of metabolic disorders, including obesity and type 2 diabetes. In this study, we identified a novel small molecule, ampkinone (6f), as an indirect AMPK activator, which was derived from the small molecule library constructed by diversity-oriented synthesis. Ampkinone stimulated the phosphorylation of AMPK via the indirect activation of AMPK in various cell lines. Ampkinone-mediated activation of AMPK required the activity of LKB1 and resulted in increased glucose uptake in muscle cells. In addition, ampkinone-treated DIO mice significantly reduced total body weight and overall fat mass. Histological examination and measurement of lipid parameters showed that ampkinone effectively improved metabolic abnormalities in the DIO mice model. Our results demonstrate that ampkinone, a small molecule with a privileged benzopyran substructure, has a potential as a new class of therapeutic agent for antidiabetic and antiobesity treatment via the indirect stimulation of AMPK.
Oh
Sangmi
S
Department of Chemistry, Seoul National University, Seoul 151-747, Korea.
Kim
Sung Jin
SJ
Hwang
Jung Hwan
JH
Lee
Hyang Yeon
HY
Ryu
Min Jeong
MJ
Park
Jongmin
J
Kim
Soung Jung
SJ
Jo
Young Suk
YS
Kim
Yong Kyung
YK
Lee
Chul-Ho
CH
Kweon
Ki Ryang
KR
Shong
Minho
M
Park
Seung Bum
SB
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004285:Dogs; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000201:enzymology; D009929:Organ Size; D010766:Phosphorylation; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D001578:Benzopyrans; D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D010797:Phthalimides; D054852:Small Molecule Libraries; C553266:ampkinone; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase