Selective Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 for Patients With Metabolic Syndrome

Abstract

An exciting era is upon us in terms of new therapies for patients with diabetes, obesity, and metabolic syndrome. One such advance is the ability to selectively manipulate tissue levels of glucocorticoids through targeted inhibition of cortisol metabolic pathways. Perhaps the best paradigm for metabolic syndrome comes from patients with Cushing's syndrome, with their characteristic central obesity, glucose intolerance, hypertension, and premature cardiovascular mortality. Although circulating cortisol concentrations are invariably normal in patients with obesity and metabolic syndrome (1), in vitro, in vivo, and clinical studies over the last decade have collectively shown the importance of local generation of cortisol, via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in liver and fat, in mediating many facets of the metabolic syndrome (2). Major pharmaceutical companies are now engaged; over 50 patents have been issued detailing compounds and strategies for selective 11β-HSD1 inhibition. Preclinical animal studies have shown proof of concept, with improved glucose tolerance and weight reduction reported in many diabetic and obese mouse models treated with 11β-HSD1 inhibitors (3 …