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).

Abstract

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 (200mg/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.

• Authors: Ji Seon Park, Sang Dal Rhee, Nam Sook Kang, Won Hoon Jung, Hee Youn Kim, Jun Hyoung Kim, Seung Kyu Kang, Hyae Gyeong Cheon, Jin Hee Ahn, Ki Young Kim
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 81 Issue 8 Pg. 1028-35 (Apr 15 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21315688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone
• Anti-Obesity Agents
• Cyclic S-Oxides
• Hypoglycemic Agents
• Leptin
• Thiazines
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Cortisone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors)
• 3T3-L1 Cells
• Adipocytes (drug effects, enzymology, metabolism)
• Adipogenesis (drug effects)
• Animals
• Anti-Obesity Agents (pharmacology, therapeutic use)
• Cortisone (pharmacology)
• Cyclic S-Oxides (pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Glucose Tolerance Test
• Humans
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Leptin (genetics)
• Lipid Metabolism (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microsomes, Liver (drug effects, enzymology, metabolism)
• Muscle Fibers, Skeletal (cytology, drug effects, enzymology, metabolism)
• Obesity (drug therapy, enzymology, metabolism)
• Protein Binding
• Reverse Transcriptase Polymerase Chain Reaction
• Thiazines (pharmacology, therapeutic use)