Anti-diabetic and anti-adipogenic effects of a novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344)

• Published in: Biochemical pharmacology 2011-04, Vol.81 (8), p.1028-1035
• Main Authors: Park, Ji Seon, Rhee, Sang Dal, Kang, Nam Sook, Jung, Won Hoon, Kim, Hee Youn, Kim, Jun Hyoung, Kang, Seung Kyu, Cheon, Hyae Gyeong, Ahn, Jin Hee, Kim, Ki Young
• Format: Article
• Language: English
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors; 11β-Hydroxysteroid dehydrogenase type 1; 3T3-L1 Cells; adipocytes; Adipocytes - drug effects; Adipocytes - enzymology; Adipocytes - metabolism; Adipogenesis; Adipogenesis - drug effects; Animals; Anti-Obesity Agents - pharmacology; Anti-Obesity Agents - therapeutic use; Biological and medical sciences; blood glucose; Cortisone - pharmacology; Cyclic S-Oxides - pharmacology; Cyclic S-Oxides - therapeutic use; Diabetes. Impaired glucose tolerance; Dose-Response Relationship, Drug; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; enzyme activity; Etiopathogenesis. Screening. Investigations. Target tissue resistance; glucose; Glucose tolerance; Glucose Tolerance Test; glucose tolerance tests; glycemic control; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Leptin - genetics; Lipid Metabolism - drug effects; liver; Male; Medical sciences; Metabolic diseases; Metabolic syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Miscellaneous; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - enzymology; Muscle Fibers, Skeletal - metabolism; noninsulin-dependent diabetes mellitus; obesity; Obesity - drug therapy; Obesity - enzymology; Obesity - metabolism; Other metabolic disorders; patients; pharmacology; Pharmacology. Drug treatments; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; Thiazines - pharmacology; Thiazines - therapeutic use; Type 2 diabetes
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.01.020

The selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus and metabolic syndrome. In the present study, we investigated the anti-diabetic and anti-adipogenic effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), as a 11β-HSD1 inhibitor; we also investigated the underlying molecular mechanisms in the cortisone-induced 3T3-L1 adipogenesis model system and C57BL/6-Lep ob/ob mice. KR-66344 concentration-dependently inhibited 11β-HSD1 activity in human liver microsome, mouse C2C12 myotube and human SW982 cells. In the C57BL/6-Lep ob/ob mice study, the administration of KR-66344 (200 mg/kg/d, orally for 5 days) improved the glucose intolerance as determined by the oral glucose tolerance test, in which the area under the curve (AUC) of the plasma glucose concentration was significantly reduced by 27% compared with the vehicle treated group. Further, KR-66344 suppressed adipocyte differentiation on cortisone-induced adipogenesis in 3T3-L1 cells is associated with the suppression of the cortisone-induced mRNA levels of FABP4, G3PD, PPARγ2 and Glut4, and 11β-HSD1 expression and activity. Our results additionally demonstrate evidence showing that KR-66344 improved glycemic control and inhibited adipogenesis via 11β-HSD1 enzyme activity. Taken together, these results may provide evidence of the therapeutic potential of KR-66344, as a 11β-HSD1 inhibitor, in obesity and type 2 diabetes patients with metabolic syndrome.