Chronic exposure to elevated circulating glucocorticoids can lead to metabolic changes, which resemble those observed in Metabolic Syndrome. Features of the Metabolic Syndrome can be reversed by lowering systemic glucocorticoid levels or by treatment with a glucocorticoid receptor antagonist. At the intracellular level, exposure to glucocorticoids is regulated by two distinct 11beta-hydroxysteroid dehydrogenases, 11beta-HSD type 1 and type 2. 11beta-HSD1 predominantly acts as a reductase, converting inactive cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone), whereas 11beta-HSD2 is a dehydrogenase responsible for glucocorticoid inactivation. Studies with transgenic mice have elucidated the importance of intracellular metabolism of glucocorticoids by 11beta-HSD1 for the development of Metabolic Syndrome.
High-throughput screening identified a novel potent and selective adamantyl triazole enzyme inhibitor of 11beta-HSD1. The ability of the compound to inhibit enzyme activity in mice was confirmed by pharmacodynamic assessment after oral dosing. In diabetic mice maintained on a high-fat diet and treated with a single moderate dose of streptozotocin, chronic oral administration (30 mpk b.i.d., 9 days) of the 11beta-HSD1 inhibitor resulted in lowered serum triglycerides (16-40%), lowered fasting glucose (77-80%) and decreased glucose excursions in glucose tolerance tests. Treatment (20 mpk b.i.d., 11 days) of diet-induced obese mice with the inhibitor lowered insulin (40-71%) and fasting glucose (10-28%) and reduced body weight (5-12%).
In summary, pharmacological inhibition of 11beta-HSD1 in mice leads to profound improvement of several key features of the Metabolic Syndrome.
22 - 24 Mar 2004
British Endocrine Societies