The role of 11beta-hydroxysteroid dehydrogenase in metabolic disease and therapeutic potential of 11beta-hsd1 inhibitors.
Glucocorticoids play an essential role in the regulation of multiple physiological processes, including energy metabolism, maintenance of blood pressure and stress responses, as well as cognitive functions. On a tissue-specific level, glucocorticoid action is controlled by 11beta-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme (11beta-HSD1) is a NADP(H)-dependent bidirectional enzyme in vitro and reduces cortisone to active cortisol in vivo. 11beta-HSD1 is expressed in many tissues including the liver, adipose and skeletal muscles. Chronically elevated local glucocorticoid action as a result of increased 11beta-HSD1 activity has been associated with the metabolic syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes and cardiovascular complications. Recent studies indicate that the inhibition of 11beta-HSD1 mitigates the adverse effects of excessive glucocorticoid levels on metabolic parameters and provides promising opportunities for the development of therapeutic interventions. This review discusses recently disclosed 11beta-HSD1 inhibitors and their potential for the treatment of metabolic disorders.
Saiah
Eddine
E
Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. esaiah@wyeth.com
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000378:metabolism*; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1