11β-Hydroxysteroid dehydrogenase type 1 inhibitors as therapeutic agents

Webster, Scott P.; Pallin, T. David

doi:10.1517/13543776.17.12.1407

Cited by 38 publications

(32 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The identification of 11‐HSD1 as a potential target for the treatment of diabetes mellitus and metabolic syndrome has prompted considerable recent activity in the pharmaceutical industry; leading to the discovery and development of a multitude of novel non‐steroidal 11‐HSD1‐selective inhibitors (>90 patents filed by ∼29 different companies and other organizations since 2002). These embrace a wide variety of compounds, based predominantly around: triazoles, aryl sulphonamide thiazoles, sulfonamides and adamantyl carboxamides (Webster and Pallin, 2007; Hughes et al. , 2008).…”

Section: Pharmacological Inhibition Of 11‐hsds In the Treatment Of Camentioning

confidence: 99%

“…Identification of this mechanism for local regulation of glucocorticoid action has prompted the concept that tissue‐specific glucocorticoid excess and deficiency, in the face of normal circulating concentrations, may contribute to disease pathogenesis (Seckl and Walker, 2001). Furthermore, the presence of tissue‐specific mechanisms for regulation of glucocorticoid activity suggests promising new therapeutic targets in a variety of conditions, and has prompted a drive by pharmaceutical companies to produce selective inhibitors of the 11‐HSD isozymes (Webster and Pallin, 2007). There is already considerable evidence that selective inhibitors of 11‐HSD1 reductase can ameliorate risk factors strongly associated with cardiovascular disease (type 2 diabetes mellitus, obesity, high blood pressure, dyslipidaemia) and this has been the subject of recent reviews (Walker, 2007a; Wamil and Seckl, 2007; Webster and Pallin, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease

Hadoke

Iqbal

Walker

2009

British J Pharmacology

View full text Add to dashboard Cite

The therapeutic potential for manipulation of glucocorticoid metabolism in cardiovascular disease was revolutionized by the recognition that access of glucocorticoids to their receptors is regulated in a tissue-specific manner by the isozymes of 11b-hydroxysteroid dehydrogenase. Selective inhibitors of 11b-hydroxysteroid dehydrogenase type 1 have been shown recently to ameliorate cardiovascular risk factors and inhibit the development of atherosclerosis. This article addresses the possibility that inhibition of 11b-hydroxsteroid dehydrogenase type 1 activity in cells of the cardiovascular system contributes to this beneficial action. The link between glucocorticoids and cardiovascular disease is complex as glucocorticoid excess is linked with increased cardiovascular events but glucocorticoid administration can reduce atherogenesis and restenosis in animal models. There is considerable evidence that glucocorticoids can interact directly with cells of the cardiovascular system to alter their function and structure and the inflammatory response to injury. These actions may be regulated by glucocorticoid and/or mineralocorticoid receptors but are also dependent on the 11b-hydroxysteroid dehydrogenases which may be expressed in cardiac, vascular (endothelial, smooth muscle) and inflammatory (macrophages, neutrophils) cells. The activity of 11b-hydroxysteroid dehydrogenases in these cells is dependent upon differentiation state, the action of pro-inflammaotory cytokines and the influence of endogenous inhibitors (oxysterols, bile acids). Further investigations are required to clarify the link between glucocorticoid excess and cardiovascular events and to determine the mechanism through which glucocorticoid treatment inhibits atherosclerosis/restenosis. This will provide greater insights into the potential benefit of selective 11b-hydroxysteroid dehydrogenase inhibitors in treatment of cardiovascular disease.

show abstract

Section: Pharmacological Inhibition Of 11‐hsds In the Treatment Of Camentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease

Hadoke

Iqbal

Walker

2009

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…The surge of research and clinical interest in this area has resulted in many companies and academic groups developing selective 11β-HSD1 inhibitors from a variety of structural classes [24][25][26][27], six of which are briefly described.…”

mentioning

confidence: 99%

Crystal Structures of 11β-Hydroxysteroid Dehydrogenase Type 1 and Their Use in Drug Discovery

Thomas

Potter

2011

Future Med. Chem.

View full text Add to dashboard Cite

Cortisol is synthesized by 11β-hydroxysteroid dehydrogenase type 1, inhibitors of which may treat disease associated with excessive cortisol levels. The crystal structures of 11β-hydroxysteroid dehydrogenase type 1 that have been released may aid drug discovery. The crystal structures have been analyzed in terms of the interactions between the protein and the ligands. Despite a variety of structurally different inhibitors the crystal structures of the proteins are quite similar. However, the differences are significant for drug discovery. The crystal structures can be of use in drug discovery, but care needs to be taken when selecting structures for use in virtual screening and ligand docking.A significant problem facing society is the increase in obesity. Often observed in obese people is metabolic syndrome, a disease characterized by a variety of symptoms including congestive heart failure, hypertension, atherogenic lipidemia, glucose intolerance, insulin resistance and Type II diabetes [1]. These symptoms, widely recognized as being risk factors for cardio vascular disease [2], are also associated with high levels of the glucocorticoid hormone cortisol [3,4]. Glucocorticoid hormones play essential roles in a range of physiological processes including the regulation of carbohydrate, lipid and bone metabolism, maturation and differentiation of cells, and modulation of inflammatory responses and stress [5][6][7]. They exert their effect primarily through binding to glucocorticoid receptors, leading to altered target gene transcription. Symptoms similar to those of metabolic syndrome are observed in patients suffering from Cushing's syndrome, which is marked by increased glucocorticoid levels [8]. The similarity of these symptoms suggests that the suppression of glucocorticoid activity may be a treatment for the individual indications of metabolic syndrome [9] despite the fact that in metabolic syndrome circulating glucocorticoid levels are not usually elevated [10]. Therefore, it is speculated that intercellular, but particularly intracellular local levels of glucocorticoid regulated by

show abstract

“…Both isozymes are inhibited by the liquorice derivative, glycyrrhetinic acid or its synthetic analogue, carbenoxolone, which have contributed greatly to our current understanding of the function of 11β-HSDs, especially in humans. More recently, selective 11β-HSD1 inhibitors have been developed, allowing much greater discrimination of the roles of these important enzymes [64]. …”

Section: Metabolism By 11β-hsds Modulates Glucocorticoid Actionmentioning

confidence: 99%

Modulation of 11β-Hydroxysteroid Dehydrogenase as a Strategy to Reduce Vascular Inflammation

Hadoke

Kipari

Chapman

2013

Curr Atheroscler Rep

View full text Add to dashboard Cite

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/ inhibition causes hypertension, whereas deficiency/ inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/ inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis.

show abstract

11β-Hydroxysteroid dehydrogenase type 1 inhibitors as therapeutic agents

Cited by 38 publications

References 37 publications

Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease

Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease

Crystal Structures of 11β-Hydroxysteroid Dehydrogenase Type 1 and Their Use in Drug Discovery

Modulation of 11β-Hydroxysteroid Dehydrogenase as a Strategy to Reduce Vascular Inflammation

Contact Info

Product

Resources

About