Institute for New Drug Development, Division of Life Sciences, Incheon National University, Incheon 406-772, Korea.
R & D Center, Ahn Gook Pharm., Suwon 443-766, Korea.
Life Sci. 2015 Jan 1;120:1-7. doi: 10.1016/j.lfs.2014.11.001. Epub 2014 Nov 12.
Elevated levels of glucocorticoid hormones cause glucose intolerance, visceral obesity, insulin resistance, hypertension, and dyslipidemia. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents as an attractive therapeutic target for treatment of metabolic syndrome and type 2 diabetes. This study investigated whether 11β-HSD1 inhibition by a novel selective inhibitor, (1S,3R,4S,5S,7S)-4-(1-((2-fluoro-N-methylphenylsulfonamido)-methyl) cyclopropanecarboxamido) adamantane-1-carboxamide (UI-1499) ameliorated metabolic abnormalities in diabetic mice.
The in vitro activity of 11β-HSD1 was measured using the homogeneous time resolved fluorescence (HTRF) assay. Differentiated adipocytes were used to evaluate cellular 11β-HSD1 activity. To determine the inhibitory effects on 11β-HSD1 in tissues, we performed ex vivo studies using liver and epididymal fat isolated from C57BL/6J mice. KKAy mice were administered with UI-1499 to evaluate whether this compound ameliorated metabolic abnormalities in vivo in diabetic animals.
UI-1499 had highly potent inhibitory activity in mouse, monkey and human 11β-HSD1, derived from liver microsomes. Oral administration of 45 mg/kg UI-1499 significantly inhibited 11β-HSD1 activity in C57BL/6J mouse liver and epididymal fat tissues. In KKAy mice, oral administration of UI-1499 (10 and 30 mg/kg for 3 weeks) lowered fasting blood glucose and HbA1c levels; these effects were comparable to those of pioglitazone. Further, UI-1499 treatment lowered plasma low-density lipoprotein (LDL) level in KKAy mice.
These results suggest that the 11β-HSD1 inhibitor, UI-1499, may serve as a novel drug candidate for the treatment of type 2 diabetes and metabolic syndrome.
糖皮质激素水平升高可导致葡萄糖不耐受、内脏肥胖、胰岛素抵抗、高血压和血脂异常。11β-羟类固醇脱氢酶 1 型（11β-HSD1）是治疗代谢综合征和 2 型糖尿病的一个有吸引力的治疗靶点。本研究旨在探讨新型选择性抑制剂（1S，3R，4S，5S，7S）-4-（1-（（2-氟-N-甲基苯磺酰胺基）甲基）环丙烷羧酰胺基）金刚烷-1-羧酰胺（UI-1499）是否可抑制 11β-HSD1 从而改善糖尿病小鼠的代谢异常。
使用均相时间分辨荧光（HTRF）测定法测定 11β-HSD1 的体外活性。使用分化的脂肪细胞来评估细胞内 11β-HSD1 活性。为了确定对组织中 11β-HSD1 的抑制作用，我们使用 C57BL/6J 小鼠分离的肝和附睾脂肪进行了离体研究。给予 KKAy 小鼠 UI-1499，以评估该化合物是否可改善糖尿病动物体内的代谢异常。
UI-1499 对来源于肝微粒体的小鼠、猴子和人 11β-HSD1 具有很强的抑制活性。45mg/kg 的 UI-1499 口服给药可显著抑制 C57BL/6J 小鼠肝和附睾脂肪组织中的 11β-HSD1 活性。在 KKAy 小鼠中，UI-1499（10 和 30mg/kg，连续 3 周）口服给药可降低空腹血糖和 HbA1c 水平；这些作用与吡格列酮相当。此外，UI-1499 治疗可降低 KKAy 小鼠的血浆低密度脂蛋白（LDL）水平。
这些结果表明，11β-HSD1 抑制剂 UI-1499 可能成为治疗 2 型糖尿病和代谢综合征的新型候选药物。
