11beta-hydroxysteroid dehydrogenase type 1 inhibitors as promising therapeutic drugs for diabetes: status and development

Abstract

Glucocorticoids (GC) play a fundamental role in controlling physiologic homeostasis and, when present in excess, can have a detrimental impact on glucose control, blood pressure and lipid levels. The oxidoreductase 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mainly catalyzes the intracellular regeneration of active GCs (cortisol, corticosterone) from inert inactive 11-keto forms (cortisone) in liver, adipose tissue and brain, amplifying local GC action. Multiple lines of evidence have indicated that 11beta-HSD1-mediated intracellular cortisol production may have a pathogenic role in type 2 diabetes and its co-morbidities. The 11beta-HSD1 becomes a novel target for anti-type 2 diabetes drug developments, and inhibition of 11beta-HSD1 offers a potential therapy to attenuate the type 2 diabetes. In the past several years, a lot of 11beta-HSD1 inhibitors have been designed, synthesized, screened and discovered. Lowering intracellular glucocorticoid concentrations through administration of small molecule 11beta-HSD1 selective inhibitors, significantly attenuates the signs and symptoms of disease in preclinical animal models and clinical trials of diabetes and metabolic syndrome. Among published inhibitors, DIO-902 from DiObex Inc. and INCB13739 from Incyte Inc. are now being investigated under Phase 2B clinical trials. However, the selectivity of current selective 11beta-HSD1 inhibitors has been just focused on the difference between 11beta-HSD1 and 11beta-HSD2. They inhibit the bi-directional activities of 11beta-HSD1, both 11beta-HSD1 reductase (major) and oxidase (minor). In our lab, we have recently found novel chemicals that not only inhibit 11beta-HSD1 reductase activity but also increase its oxidase activity without inhibition against 11beta-HSD2. We propose that this dual modulation on 11beta-HSD1 may provide a better therapeutic strategy for type 2 diabetes.