11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors as Promising Therapeutic Drugs for Diabetes: Status and Development

Title: 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors as Promising Therapeutic Drugs for Diabetes: Status and Development

Volume: 17 Issue: 5

Author(s): R. Ge, Y. Huang, G. Liang and X. Li

Affiliation:

Keywords: 11β-HSD1 inhibitor, selectivity, type 2 diabetes, clinical trial, dual modulation

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 11β- hydroxysteroid dehydrogenase type 1 (11β-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 11β-HSD1-mediated intracellular cortisol production may have a pathogenic role in type 2 diabetes and its co-morbidities. The 11β-HSD1 becomes a novel target for anti-type 2 diabetes drug developments, and inhibition of 11β-HSD1 offers a potential therapy to attenuate the type 2 diabetes. In the past several years, a lot of 11β-HSD1 inhibitors have been designed, synthesized, screened and discovered. Lowering intracellular glucocorticoid concentrations through administration of small molecule 11β-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 11β-HSD1 inhibitors has been just focused on the difference between 11β-HSD1 and 11β-HSD2. They inhibit the bi-directional activities of 11β-HSD1, both 11β-HSD1 reductase (major) and oxidase (minor). In our lab, we have recently found novel chemicals that not only inhibit 11β-HSD1 reductase activity but also increase its oxidase activity without inhibition against 11β-HSD2. We propose that this dual modulation on 11β-HSD1 may provide a better therapeutic strategy for type 2 diabetes.

Cite this article as:

Ge R., Huang Y., Liang G. and Li X., 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors as Promising Therapeutic Drugs for Diabetes: Status and Development, Current Medicinal Chemistry 2010; 17 (5) . https://dx.doi.org/10.2174/092986710790226147