Antidiabetic and antiobesity effects of Ampkinone (6f), a novel small molecule activator of AMP-activated protein kinase.

Abstract

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.

• Authors: Sangmi Oh, Sung Jin Kim, Jung Hwan Hwang, Hyang Yeon Lee, Min Jeong Ryu, Jongmin Park, Soung Jung Kim, Young Suk Jo, Yong Kyung Kim, Chul-Ho Lee, Ki Ryang Kweon, Minho Shong, Seung Bum Park
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 20 Pg. 7405-13 (Oct 28 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20873794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Obesity Agents
• Benzopyrans
• Blood Glucose
• Enzyme Activators
• Hypoglycemic Agents
• Insulin
• Phthalimides
• Small Molecule Libraries
• ampkinone
• AMP-Activated Protein Kinases
• Acetyl-CoA Carboxylase

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Acetyl-CoA Carboxylase (metabolism)
• Adipose Tissue (drug effects, metabolism, pathology)
• Animals
• Anti-Obesity Agents (chemical synthesis, chemistry, pharmacology)
• Benzopyrans (chemical synthesis, chemistry, pharmacology)
• Blood Glucose (metabolism)
• Body Weight (drug effects)
• Cell Line
• Diabetes Mellitus, Type 2 (drug therapy)
• Dogs
• Enzyme Activators (chemical synthesis, chemistry, pharmacology)
• Humans
• Hypoglycemic Agents (chemical synthesis, chemistry, pharmacology)
• In Vitro Techniques
• Insulin (blood)
• Liver (enzymology)
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Skeletal (enzymology)
• Organ Size
• Phosphorylation
• Phthalimides (chemical synthesis, chemistry, pharmacology)
• Rats
• Small Molecule Libraries
• Structure-Activity Relationship