123rd General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2
Time 4월 18일 (목요일) 11:00~12:30
Code MEDI.P-379
Subject A novel highly potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor in a diabetic mouse model
Authors Hanbyeol Park, Dong Oh Han1, Soon Kil Ahn*
Institute for New Drug Development, Division of Life Sciences, Korea
1Biodrug Department, Ahngook Pharm., Korea
Abstract 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a cortisol regenerating enzyme that amplifies tissue glucocorticoid levels, especially in the liver and adipose tissue. Knockout mice or a selective inhibitor of 11β- HSD1 improves metabolic syndrome parameters in preclinical models and human clinical trials. Here, we evaluated the therapeutic potential of INU-101, a potent and selective oral inhibitor of 11β-HSD1. The in vitro activity of 11β-HSD1 was measured using the homogeneous time-resolved fluorescence (HTRF) assay. Differentiated adipocytes were used to evaluate the cellular 11β-HSD1 activity. To determine the inhibitory effects on 11β-HSD1 in tissues, we performed ex vivo studies using liver and adipose tissue isolated from C57BL/6J mice and Cynomolgus monkeys. KKAy mice and ZDF rats were administered INU-101 to evaluate whether this compound ameliorated metabolic abnormalities in obese and diabetic animals. INU-101 had highly potent inhibitory activity in mouse, monkey and human 11β-HSD1, derived from liver microsomes. The oral administration of INU-101 significantly inhibited 11β-HSD1 activity in the liver and adipose tissue of mice and monkeys. In KKAy mice and ZDF rats, the oral administration of INU-101 enhanced insulin sensitivity and lowered the fasting blood glucose level. Furthermore, INU-101 treatment decreased the body weight and ameliorated an improved lipid profile in the diabetic mouse model. These results suggest that the 11β-HSD1 inhibitor, INU-101 may serve as a novel drug candidate for the treatment of type 2 diabetes and metabolic syndrome.
E-mail qkrgksquf100@naver.com