Recent progress in 11-β-hydroxysteroid dehydrogenase type 1 (11-β-HSD1) inhibitor development

Glucocorticoids regulate a plethora of processes via stimulation of nuclear glucocorticoid receptors. Exaggerated effects of glucocorticoids can give rise to multiple clinical features typified by Cushing's disease, a metabolic syndrome comprising hyperglycemia, insulin-resistant diabetes, obesity, dyslipiclemia and hypertension. Since the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD1) locally regenerates active glucocorticoids, tissue-specific inhibitors of 11-beta-HSD1 have potential for ameliorating the above conditions. This review describes the recent efforts to identify potent and selective 11-beta-HSD1 inhibitors, aimed at correcting abnormalities associated with the metabolic syndrome. The primary focus is on aspects of the metabolic syndrome, but it is recognized that inactivation of 11-beta-HSD1 may also be beneficial in other diseases.