11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders?

Abstract

OBJECTIVE:

Metabolic syndrome (MetS) and Cushing's syndrome share common features. It has been proposed that increased glucocorticoid activity at peripheral tissues may play a role in the pathogenesis of MetS and obesity-related disorders. It is well-known that intracellular cortisol concentrations are determined not only by plasma levels but also by the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the conversion of inactive cortisone to active cortisol, especially in the liver and adipose tissue. Another isoenzyme exists, the 11β-hydroxysteroid dehydrogenase type 2, which acts in the opposite direction inactivating cortisol to cortisone in the kidney. This review considers the significance of the 11β-HSD1 inhibition in the treatment of several features of MetS and provides current data about the development of 11β-HSD1 inhibitors, as new agents for this purpose.

MATERIALS/METHODS:

Using PubMed, we searched for publications during the last 20years regarding the development of 11β-HSD1 inhibitors.

RESULTS:

Emerging data from animal and human studies indicate an association of 11β-HSD1 over-expression with obesity and disorders in glucose and lipid metabolism. This has led to the hypothesis that selective inhibition of 11β-HSD1 could be used to treat MetS and diabetes. Indeed, natural products and older agents such as thiazolidinediones and fibrates seem to exert an inhibitory effect on 11β-HSD1, ameliorating the cardiometabolic profile. In view of this concept, novel compounds, such as adamantyltriazoles, arylsulfonamidothiazoles, anilinothiazolones, BVT2733, INCB-13739, MK-0916 and MK-0736, are currently under investigation and the preliminary findings from both experimental and human studies show a favourable effect on glucose and lipid metabolism, weight reduction and adipokine levels.

CONCLUSIONS:

Many compounds inhibiting 11β-ΗSD1 are under development and preliminary data about their impact on glucose metabolism and obesity-related disorders are encouraging.

• Authors: Panagiotis Anagnostis, Niki Katsiki, Fotini Adamidou, Vasilios G Athyros, Asterios Karagiannis, Marina Kita, Dimitri P Mikhailidis
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 62 Issue 1 Pg. 21-33 (Jan 2013) ISSN: 1532-8600 [Electronic] United States
• PMID: 22652056 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Sulfonamides
• Thiazoles
• 11-beta-Hydroxysteroid Dehydrogenase Type 1

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors, metabolism)
• Animals
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Humans
• Metabolic Syndrome (drug therapy, enzymology, metabolism)
• Obesity (drug therapy, enzymology, metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Thiazoles (pharmacology, therapeutic use)