Effect of Dosing Regimen with an 11β-HSD1 Inhibitor on the Improvement of Metabolic Parameters in DIO Mice.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates glucocorticoid action by activating glucocorticoids at the tissue level. Both genetic and pharmacologic studies suggest that 11β-HSD1 inhibition is a viable therapeutic strategy for the treatment of type 2 diabetes and metabolic syndrome. There are two sources of active glucocorticoids in the target tissue: the plasma cortisol (or corticosterone in rodents) and that produced locally by 11β-HSDI. The physiological effect is mediated by the total local glucocorticoid level in a given tissue. Due to the circadian variation of plasma glucocorticoids, the pharmacologic efficacy of 11βHSD1 inhibition may depend on the timing of inhibitor administration. In order to determine the optimal time to acheive maximum efficacy, we used a diet induced obesity (DIO) mouse model and a novel small molecule inhibitor of 11β-HSD1 from our thiazolone series. Mice were fed a high fat diet for 12 weeks, randomized on their fed blood glucose and treated with an 11β-HSD1 inhibitor for 3 weeks. This compound is potent and selective for the 11β-HSD1 enzyme from several species. One group of mice was treated at 25 mpk in the morning (AM), a second group at 25 mpk in the evening (PM) and a third group at 12.5 mpk BID. Three groups of mice were treated with vehicle following the same schedule as the 11β-HSD1 inhibitor. At the end of the treatment, a sub-group of mice from each group were challenged with a glucose tolerance test (GTT) and the rest were used for determination of lipid and insulin levels. During the GTT, glucose clearance was improved only in mice treated with the 11β-HSD1 inhibitor in the PM or BID. Fasted and fed blood glucose levels were decreased in the same groups. In conclusion, in this animal model an 11β-HSD1 inhibitor showed maximum efficacy when dosed in the PM (when the plasma corticosterone is high), Dosing in the AM, when the plasma corticosterone is low, does not appear to be important in achieving efficacy. [ABSTRACT FROM AUTHOR]