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.
J Mol Endocrinol. 2014 Mar 6;52(2):191-202. doi: 10.1530/JME-13-0177. Print 2014 Apr.
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.
选择性 11β-羟类固醇脱氢酶 1（11β-HSD1）抑制剂在治疗骨质疏松症以及包括 2 型糖尿病在内的代谢综合征方面具有很大的潜力。在这里，我们研究了新型选择性 11β-HSD1 抑制剂 KR-67500 的抗糖尿病、抗脂肪生成和抗骨质疏松活性。细胞 11β-HSD1 活性基于均相时间分辨荧光法进行测试。在给予 KR-67500（每天 50mg/kg，口服）28 天的饮食诱导肥胖（DIO）-C57BL/6 小鼠中测量口服葡萄糖耐量试验（OGTT）和胰岛素耐量试验（ITT）水平，并通过 OGTT 和 ITT 评估其抗糖尿病作用。通过油红 O 染色测定 KR-67500 的体外抗脂肪生成作用。通过骨形态发生蛋白 2（BMP2）诱导的成骨细胞分化和核因子-κB 受体激活剂配体（RANKL）诱导的破骨细胞分化模型系统评估 KR-67500 的体外抗骨质疏松活性。KR-67500 改善了 DIO-C57BL/6 小鼠的体内葡萄糖耐量和胰岛素敏感性。KR-67500 抑制皮质酮诱导的 3T3-L1 细胞向脂肪细胞的分化。KR-67500 增强了 C2C12 细胞中 BMP2 诱导的成骨作用，并抑制了小鼠骨髓来源巨噬细胞中 RANKL 诱导的破骨细胞生成。新型选择性 11β-HSD1 抑制剂 KR-67500 可能为预防和/或治疗 2 型糖尿病、肥胖症和/或骨质疏松症提供新的治疗窗口。
