1. Antidiabetic and antiobesity effects of Ampkinone (6f), a novel small molecule activator of AMP-activated protein kinase
- Author
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Chul-Ho Lee, Sungjin Kim, Hyang Yeon Lee, Ki Ryang Kweon, Jongmin Park, Minho Shong, Seung Bum Park, Young Suk Jo, Yong Kyung Kim, Min Jeong Ryu, Soung Jung Kim, Sangmi Oh, and Jung Hwan Hwang
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Glucose uptake ,Enzyme Activators ,Phthalimides ,Pharmacology ,AMP-Activated Protein Kinases ,In Vitro Techniques ,Cell Line ,Small Molecule Libraries ,Mice ,Structure-Activity Relationship ,Dogs ,AMP-activated protein kinase ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Insulin ,Benzopyrans ,Phosphorylation ,Protein kinase A ,Muscle, Skeletal ,biology ,Chemistry ,Activator (genetics) ,Body Weight ,AMPK ,Organ Size ,Adenosine ,Small molecule ,Rats ,Mice, Inbred C57BL ,Endocrinology ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Liver ,biology.protein ,Molecular Medicine ,Anti-Obesity Agents ,medicine.drug ,Acetyl-CoA Carboxylase - 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.
- Published
- 2010