A novel highly potent and selective 11 beta-hydroxysteroid dehydrogenase type 1 inhibitor, UI-1499

作者：Byun Soo Young; Shin Young June; Nam Ky Youb; Hong Sung Pyo; Ahn Soon Kil^*

来源：Life Sciences, 2015, 120: 1-7.

DOI：10.1016/j.lfs.2014.11.001

• 11 beta-HSD1 inhibitor
• blood glucose
• glucocorticoid
• type 2 diabetes
• metabolic syndrome
• KKAy mice

Aims: Elevated levels of glucocorticoid hormones cause glucose intolerance, visceral obesity, insulin resistance, hypertension, and dysfipidemia. 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) represents as an attractive therapeutic target for treatment of metabolic syndrome and type 2 diabetes, This study investigated whether 11 beta-HSD1 inhibition by a novel selective inhibitor, (1S,3R,4S,5S,7S)-4-(1-((2-fluoro-N-methylphenylsulfonamido)-methyl) cyclopropanecarboxamido) adamantane-l-carboxamide (UI-1499) ameliorated metabolic abnormalities in diabetic mice.
Main methods: The in vitro activity of 11 beta-HSD1 was measured using the homogeneous time resolved fluorescence (HTRF) assay. Differentiated adipocytes were used to evaluate cellular 11 beta-HSD1 activity. To determine the inhibitory effects on 11 beta-HSD1 in tissues, we performed ex vivo studies using liver and epididymal fat isolated from C57BL/61 mice, KKAy mice were administered with UI-1499 to evaluate whether this compound ameliorated metabolic abnormalities in vivo in diabetic animals.
Key findings: UI-1499 had highly potent inhibitory activity in mouse, monkey and human 11 beta-HSD1, derived from liver microsomes. Oral administration of 45 mg/kg UI-1499 significantly inhibited 11 beta-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.
Significance: These results suggest that the 11 beta-HSD1 inhibitor, UI-1499, may serve as a novel drug candidate for the treatment of type 2 diabetes and metabolic syndrome.

• 出版日期2015-1-1