Arylsulfonamidothiazoles as a New Class of Potential Antidiabetic Drugs. Discovery of Potent and Selective Inhibitors of the 11β-Hydroxysteroid Dehydrogenase Type 1

Barf, Tjeerd; Vallgårda, Jerk; Emond, Rikard; Häggström, Charlotta; Kurz, Guido; Nygren, Alf; Larwood, Vivienne; Mosialou, Erifili; Axelsson, Kent; Olsson, Rolf; Engblom, Lars O. M.; Edling, N.; Rönquist-Nii, Yuko; Öhman, Birgitta; Alberts, Pēteris; Abrahmsén, Lars

doi:10.1021/jm025530f

Cited by 216 publications

(154 citation statements)

References 11 publications

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“…Discussion 11b-HSD1 is a tissue-specific prereceptor regulator of the GC responses (Tomlinson et al 2004). Its importance as a possible therapeutic target in the management of human obesity and insulin resistance is supported by the development of selective 11b-HSD1 inhibitors that improve glucose tolerance in diabetic mice (Alberts et al 2002, Barf et al 2002. In the human eye, the isozyme has been implicated in the pathogenesis of ocular surface disease and glaucoma, the leading causes of worldwide blindness (Stokes et al 2000, Rauz et al 2003a.…”

Section: Western Blot Analysesmentioning

confidence: 99%

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Onyimba¹,

Vijapurapu²,

Curnow³

et al. 2006

Journal of Endocrinology

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The prereceptor regulation of glucocorticoids (GCs) by 11b-hydroxysteroid dehydrogenase type-1 (11b-HSD1), a bidirectional isozyme that interconverts active (cortisol) and inactive (cortisone) GCs, is an established determinant of GC function in tissues such as liver, adipose and bone. Although the therapeutic use of GCs is abundant in ophthalmic practice, where GC interactions with nuclear receptors modulate gene transcription, the prereceptor regulation of endogenous cortisol is not well described in ocular tissues. Recent descriptive studies have localised 11b-HSD1 to the human corneal epithelium and non-pigmented epithelium (NPE) of the ciliary body, indicating a link to corneal epithelial physiology and aqueous humour production. In this study, we characterise the functional aspects of the autocrine regulation of GCs in the anterior segment of the rabbit eye. Using our in-house generated primary antibody to human 11b-HSD1, immunohistochemical analyses were performed on paraffin-embedded sections of whole New Zealand white albino rabbits, (NZWAR) eyes. As in human studies, 11b-HSD1 was localised to the corneal epithelium and the NPE. No staining was seen in the albino 'pigmented' ciliary epithelium. Specific enzyme assays for oxo-reductase (cortisone/cortisol) and dehydrogenase (cortisol/cortisone) activity indicated predominant 11b-HSD1 oxo-reductase activity from both the intact ciliary body tissue (nZ12, median 2$1 pmol/mg per h and range 1$25-2$8 pmol/mg per h; PZ0$006) and primary cultures of corneal epithelial cells (nZ12, median 3$0 pmol/mg per h and range 1$0-7$4 pmol/mg per h, PZ0$008) compared with dehydrogenase activity (median 1$0 pmol/mg per h and range 0$5-2$0 pmol/mg per h; median 0$5 pmol/mg per h and range 0$25-1$9 pmol/mg per h respectively). These findings were supported by expression of 11b-HSD1 protein as visualised by Western blotting of ciliary body tissue and immunocytochemistry of corneal epithelial cells. Reduction of corneal epithelial cell proliferation was seen after primary cultures were co-incubated with cortisol and cortisone. 11b-HSD1 activity was not demonstrated in naïve conjunctival fibroblasts or corneal stromal keratocytes. Our results indicate that the distribution of 11b-HSD1 in the rabbit resembles that of the human eye and activates cortisone to cortisol in both corneal and uveal tissues. The NZWAR provides a suitable in vivo model for the further evaluation of 11b-HSD1 activity in the eye, especially its role in corneal epithelial and ciliary body physiology.

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Section: Western Blot Analysesmentioning

confidence: 99%

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Onyimba¹,

Vijapurapu²,

Curnow³

et al. 2006

Journal of Endocrinology

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“…Selective inhibitors of human 11β-HSD1 have already been synthesised [80]. These drugs could lower intrahepatic and intra-adipose tissue cortisol concentrations and thereby regionally enhance insulin sensitivity, reduce gluconeogenesis and potentially even adiposity.…”

Section: Studies With 11β-hsd Inhibitorsmentioning

confidence: 99%

11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes

2004

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Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing's syndrome, as well as glucocorticoids' functional antagonism to insulin. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby regulating local glucocorticoid action. Recent data, mainly from rodents, provide considerable evidence for a causal role of 11β-HSD1 for the development of visceral obesity and Type 2 diabetes though data in humans are not unequivocal. This review summarizes current evidence on a possible role of 11β-HSD1 for development of the metabolic syndrome, raising the possibility of novel therapeutic options for the treatment of Type 2 diabetes by inhibition or down-regulation of 11β-HSD1 activity.[Diabetologia (2004) by increased waist-to-hip ratio-rather than lowerbody (gynoid) obesity is associated with glucose intolerance and other features of the metabolic syndrome, and represents an important predictor for increased morbidity and mortality, not only from diabetes but also from coronary heart disease and certain cancers [4]. Although the WHR encompasses both intra-abdominal (visceral) and abdominal subcutaneous adipose depots, more detailed studies emphasize the importance of the visceral component for the development of metabolic disorders [4]. A causal relationship of visceral obesity for insulin resistance was recently demonstrated by surgical removal of visceral (epididymal and perinephric) fat pads of obese Sprague-Dawley rats that markedly improved hepatic insulin sensitivity and reduced hepatic glucose production [5].

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“…Because adipose 11␤-HSD1 activity positively correlates to body mass index, percentage of body fat, and waist circumference as well as fasting glucose, insulin levels, and insulin resistance (23)(24)(25), 11␤-HSD1 is currently considered a promising pharmaceutical target for the treatment of diabetes type 2. Indeed, recent animal studies showed that the administration of a selective 11␤-HSD1 inhibitor to diabetic mice reduced blood glucose levels and increased insulin sensitivity (26,27). In addition to its role in the activation of glucocorticoids, 11␤-HSD1 might play a role in the detoxification of reactive ketocompounds such as the potent tobacco carcinogen nicotinederived nitrosamine ketone (NNK) and the anti-cancer drug oracin (28,29).…”

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confidence: 99%

Rapid Hepatic Metabolism of 7-Ketocholesterol by 11β-Hydroxysteroid Dehydrogenase Type 1

Schweizer

Zürcher

Balázs

et al. 2004

Journal of Biological Chemistry

119

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The role of 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1) in the local activation of the glucocorticoid receptor by converting inactive 11-ketoglucocorticoids to active 11␤-hydroxyglucocorticoids is well established. Currently, 11␤-HSD1 is considered a promising target for treatment of obese and diabetic patients. Here, we demonstrate a role of 11␤-HSD1 in the metabolism of 7-ketocholesterol (7KC), the major dietary oxysterol. Comparison of recombinant 11␤-HSD1, transiently expressed in human embryonic kidney 293 cells, revealed the stereo-specific interconversion of 7KC and 7␤-hydroxycholesterol by rat and human 11␤-HSD1, whereas the hamster enzyme interconverted 7␣-hydroxycholesterol, 7␤-hydroxycholesterol, and 7KC. In contrast to lysates, which efficiently catalyzed both oxidation and reduction, intact cells exclusively reduced 7KC. These findings were confirmed using rat and hamster liver homogenates, intact rat hepatocytes, and intact hamster liver tissue slices. Reduction of 7KC was abolished upon inhibition of 11␤-HSD1 by carbenoxolone (CBX) or 2-hydroxyflavanone. In vivo, after gavage feeding rats, 7KC rapidly appeared in the liver and was converted to 7␤-hydroxycholesterol. CBX significantly decreased the ratio of 7␤-hydroxycholesterol to 7KC, supporting the evidence from cell culture experiments for 11␤-HSD1-dependent reduction of 7KC to 7␤-hydroxycholesterol. Upon inhibition of 11␤-HSD1 by CBX, 7KC tended to accumulate in the liver, and plasma 7KC concentration increased. Together, our results suggest that 11␤-HSD1 efficiently catalyzes the first step in the rapid hepatic metabolism of dietary 7KC, which may explain why dietary 7KC has little or no effect on the development of atherosclerosis.Several in vitro studies demonstrated disturbances of cholesterol metabolism by 7KC 1 (1), including effects on hydroxymethylglutaryl-CoA-reductase and cholesterol 7␣-hydroxylase activities (2), inhibition of cholesterol release from cells (3), and down-regulation of low density lipoprotein receptor expression (4). In addition, 7KC exerts multiple effects by inhibiting nitric oxide release, decreasing glucose permeability, disrupting Ca 2ϩ -flux and inducing apoptosis in vascular cells (1).Oxidized cholesterol metabolites play a potential role in the development of atherosclerosis (1, 5, 6). Among other oxysterols, 7KC is found at micromolar concentrations in human macrophage-foam cells and atherosclerotic lesions. In contrast, plasma 7KC concentrations are in the nanomolar range. The major oxysterols present in atherosclerotic plaques are 27-hydroxycholesterol and 7KC, although the direct role of 7KC in the development and progression of atherosclerosis is still unclear. 27-Hydroxycholesterol is produced by sterol 27-hydroxylase, the first enzyme of the alternative pathway from cholesterol to bile acids in the liver (7). 7KC is believed to be formed non-enzymatically by free radical oxidation of cholesterol (8) or absorbed from dietary intake of processed cholesterol-rich food (9, 10).It was reported that u...

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Arylsulfonamidothiazoles as a New Class of Potential Antidiabetic Drugs. Discovery of Potent and Selective Inhibitors of the 11β-Hydroxysteroid Dehydrogenase Type 1

Cited by 216 publications

References 11 publications

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes

Rapid Hepatic Metabolism of 7-Ketocholesterol by 11β-Hydroxysteroid Dehydrogenase Type 1

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