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A novel 11β-HSD1 inhibitor improves diabesity and osteoblast differentiation.

Journal of molecular endocrinology (2014-01-22)
Ji Seon Park, Su Jung Bae, Sik-Won Choi, You Hwa Son, Sung Bum Park, Sang Dal Rhee, Hee Youn Kim, Won Hoon Jung, Seung Kyu Kang, Jin Hee Ahn, Seong Hwan Kim, Ki Young Kim

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.

Product Number
Product Description

Hydrocortisone, United States Pharmacopeia (USP) Reference Standard
Hydrocortisone, VETRANAL®, analytical standard
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Hydrocortisone, European Pharmacopoeia (EP) Reference Standard
Hydrocortisone for peak identification, European Pharmacopoeia (EP) Reference Standard