11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors as Promising Therapeutic Drugs for Diabetes: Status and Development
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.
No Supplementary Data
No Article Media
Document Type: Research Article
Affiliations: School of Pharmacy, Wenzhou Medical College, 1# Jingguan Road, College Town, Wenzhou City 325035, China.
Publication date: 2010-02-01
More about this publication?
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.