A novel 11β-HSD1 inhibitor improves diabesity and osteoblast differentiation.
Selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential as treatment for osteoporosis as well as metabolic syndrome including type 2 diabetes mellitus. Here, we investigated the anti-diabetic, anti-adipogenic, and anti-osteoporotic activity of KR-67500, as a novel selective 11β-HSD1 inhibitor. Cellular 11β-HSD1 activity was tested based on a homogeneous time-resolved fluorescence method. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) levels were measured in diet-induced obese (DIO)-C57BL/6 mice administered KR-67500 (50  mg/kg per day, p.o.) for 28 days and, additionally, its anti-diabetic effect was evaluated by OGTT and ITT. The in vitro anti-adipogenic effect of KR-67500 was determined by Oil Red O Staining. The in vitro anti-osteoporotic activity of KR-67500 was evaluated using bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation model systems. KR-67500 improved the in vivo glucose tolerance and insulin sensitivity in DIO-C57BL/6 mice. KR-67500 suppressed cortisone-induced differentiation of 3T3-L1 cells into adipocytes. KR-67500 enhanced BMP2-induced osteoblastogenesis in C2C12 cells and inhibited RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages. KR-67500, a new selective 11β-HSD1 inhibitor, may provide a new therapeutic window in the prevention and/or treatment of type 2 diabetes, obesity, and/or osteoporosis.
Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea Division of Life and Pharmaceutical Sciences and Center for Cell Signaling and Drug Discovery Research, College of Pharmacy, Ewha Woman's University, Sedaemoon-gu, Seoul 120-750, Republic of Korea Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Pharmacology Research Center, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea Department of Toxicology, College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Republic of Korea Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea.
Ji Seon
JS
Park
Su Jung
SJ
Bae
Sik-Won
SW
Choi
You Hwa
YH
Son
Sung Bum
SB
Park
Sang Dal
SD
Rhee
Hee Youn
HY
Kim
Won Hoon
WH
Jung
Seung Kyu
SK
Kang
Jin Hee
JH
Ahn
Seong Hwan
SH
Kim
Ki Young
KY
Kim
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
adipose tissue; diabetes II; obesity; osteoporosis