TITLE

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

AUTHOR(S)
Ge, R.; Huang, Y.; Liang, G.; Li, X.
PUB. DATE
February 2010
SOURCE
Current Medicinal Chemistry;Feb2010, Vol. 17 Issue 5, Special section p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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.
ACCESSION #
56490837

 

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics