11-Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors in Type 2 diabetes mellitus and obesity

@article{Hughes200811BetahydroxysteroidDT,
  title={11-Beta-hydroxysteroid dehydrogenase type 1 (11$\beta$-HSD1) inhibitors in Type 2 diabetes mellitus and obesity},
  author={Katherine A. Hughes and Scott Peter Webster and Brian R. Walker},
  journal={Expert Opinion on Investigational Drugs},
  year={2008},
  volume={17},
  pages={481 - 496}
}
Background: Glucocorticoids such as cortisol are important regulators of fuel metabolism during starvation and stress. Chronic glucocorticoid excess induces obesity with multiple features of the metabolic syndrome. Objective: In this article, we review the importance of glucocorticoids in metabolic syndrome and the approaches that have been explored to reduce glucocorticoid action as the basis for novel therapy of Type 2 diabetes and obesity. Method: We focus on the enzyme 11-beta… 
11β-Hydroxysteroid dehydrogenase type 1, a target for development of oral antidiabetic drugs (Review)
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Inhibition of 11β-HSD1, representatives of several types of N-containing heterocycles at various research stages, are reviewed as potential drugs influencing metabolic syndrome, DM2, and obesity.
11β-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents
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This review covers the recent 11β-HSD1 patent literature and clinical activity ranging from late 2007 through the end of 2008, as a number of structural classes have been reported by several pharmaceutical companies over the past 16 months.
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Discovery of novel inhibitors of human 11β-hydroxysteroid dehydrogenase type 1
11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome
TLDR
Evidence is being gathered not only on the relevance of such enzymes to GC physiological actions but also on their involvement in the pathophysiology of certain chronic disease states, in which circulating GC levels are not necessarily altered.
11-Dehydrocorticosterone causes metabolic syndrome, which is prevented when 11β-HSD1 is knocked out in livers of male mice.
Metabolic syndrome is growing in importance with the rising levels of obesity, type 2 diabetes, and insulin resistance. Metabolic syndrome shares many characteristics with Cushing's syndrome, which
Overexpression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Hepatic and Visceral Adipose Tissue is Associated with Metabolic Disorders in Morbidly Obese Patients
TLDR
The observed correlations between hepatic and VAT 11β-HSD1 expression with dyslipidemia and insulin resistance suggest that this enzyme might have a pathogenic role in obesity and related metabolic disorders.
The role of 11β-hydroxysteroid dehydrogenase type 1 in bile acid homeostasis
TLDR
The main goal of the present work was to investigate the impact of altered hepatic glucocorticoid activation by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) on BA homeostasis and to unravel the mechanisms of adaptations in a scenario of impaired 11 β- HSD1 function.
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References

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TLDR
This patent review focuses on the large number of patents published since 2005 and 11β-HSD1, an important target for the treatment of the metabolic syndrome and cognitive impairment, with many companies pursuing the development of inhibitors.
Novel non-steroidal inhibitors of human 11β-hydroxysteroid dehydrogenase type 1
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TLDR
Adipose 11beta-HSD1 deficiency contributes to a protective metabolic phenotype, supporting its role as a therapeutic target for the metabolic syndrome.
Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis.
TLDR
CBX is able to inhibit rapidly the generation of active GC in human adipose tissue and has functional consequences including decreased glycerol release, indicative of inhibition of GC-mediated lipolysis.
11β-Hydroxysteroid dehydrogenase Type 1 activity in lean and obese males with Type 2 diabetes mellitus
TLDR
Impaired conversion of cortisone to cortisol by the type 1 isoenzyme of 11β-hydroxysteroid dehydrogenase (11β-HSD) in obesity may represent a protective mechanism preventing ongoing weight gain and glucose intolerance.
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TLDR
Clinically useful therapeutic effects will probably require selective 11 beta-HSD1 inhibitors that lower intraadipose cortisol levels and enhance peripheral glucose uptake and further studies in obesity and hyperlipidemia are now warranted.
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TLDR
The discovery and synthesis of some 18beta-glycyrrhetinic acid (18beta-GA) derivatives and their inhibitory activities against rat hepatic11beta-HSD1 and rat renal 11beta- HSD2 are reported and their ability to inhibit human 11 beta-HSd1 was evaluated.
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TLDR
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Is 11β-Hydroxysteroid Dehydrogenase Type 1 a Therapeutic Target? Effects of Carbenoxolone in Lean and Obese Zucker Rats
TLDR
Carbenoxolone provides a model for liver-specific inhibition of 11β-HSD1, which results in improved lipid profile, in Zucker obese rats and may explain the lack of effect on glucose tolerance and obesity.
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