Perhydroquinolylbenzamides as Novel Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1

Coppola, Gary M.; Kukkola, Paivi J.; Stanton, James L.; Neubert, Alan D.; Marcopulos, Nicholas; Bilci, Natalie A.; Wang, Hua; Tomaselli, Hollis C.; Tan, Jenny; Aicher, Thomas D.; Knorr, Douglas C.; Jeng, Arco Y.; Dardik, Beatriz N.; Chatelain, Ricardo E.

doi:10.1021/jm058228q

Cited by 40 publications

(21 citation statements)

References 61 publications

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“…Several and distinct selective 11 β ‐HSD1 inhibitors are being produced, developed and tested in vitro , ex vivo and in vivo , in normal animals, rodent models of metabolic alterations or disease and some of them already in humans, healthy or not [4,13,49,51,110–152]. Besides inhibition of 11 β ‐HSD1 reductase activity, increase of 11 β ‐HSD1 dehydrogenase activity, without inhibition of 11 β ‐HSD2, may provide a better therapeutic strategy for T2DM, obesity and metabolic syndrome [143].…”

Section: β‐Hsd1 Inhibition Studiesmentioning

confidence: 99%

11β‐Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus

Pereira

Azevedo

Monteiro

et al. 2012

Diabetes Obesity Metabolism

106

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Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing's syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11β-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11β-HSD1) or inactivate cortisol to cortisone (11β-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated. HSD11B1 gene deficiency or HSD11B2 gene overexpression associates with improvements in the metabolic profile. In face of these demonstrations, research efforts are now being turned both into the inhibition of 11β-HSD1 as a possible pharmacological target and into the role of dietary habits on the establishment or the prevention of the metabolic syndrome, obesity and T2DM through 11β-HSD1 modulation. We intend to review and discuss 11β-HSD1 and obesity, the metabolic syndrome and T2DM and to highlight the potential of its inhibition for therapeutic or prophylactic approaches in those metabolic diseases.

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Section: β‐Hsd1 Inhibition Studiesmentioning

confidence: 99%

11β‐Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus

Pereira

Azevedo

Monteiro

et al. 2012

Diabetes Obesity Metabolism

106

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“…Carbenoxolone, a synthetic hemisuccinyl ester derivative of glycyrrhetinic acid, is a potent 11β‐HSD1 inhibitor (IC 50 110 nmol/L) 15 . It has been shown to improve hepatic insulin sensitivity in normal 16 and diabetic individuals 17 .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of 11β‐hydroxysteroid dehydrogenase 1 by carbenoxolone affects glucose homeostasis and obesity in db/db mice

Dhanesha

Joharapurkar

Shah³

et al. 2011

Clin Exp Pharma Physio

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1. One of the major causes of metabolic syndrome is elevated 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in the liver and adipose tissue. High 11β-HSD1 expression contributes significantly to the diabetic phenotype in db/db mice. The purpose of the present study was to test the effect of the pharmacological inhibition of 11β-HSD1 inhibition by carbenoxolone in db/db mice, a genetic model of diabetes. 2. Inhibition of 11β-HSD1 by carbenoxolone was evaluated in liver homogenates obtained from untreated mice. At 0.4, 0.8, 1.6 and 3.2 μmol/L, carbenoxolone reduced the conversion of cortisone to cortisol by 21%, 48%, 82% and 95%, respectively. 3. In another series of experiments in which female db/db mice were dosed orally with carbenoxolone (10, 25 and 50 mg/kg, twice daily) for 10 days, dose-dependent decreases were observed in 11β-HSD1 activity in the brain, adipose and liver. In the case of 10 mg/kg carbenoxolone, the effects were not significant. In addition, the bodyweight of female db/db mice was reduced by 10% and 13% following treatment with 10 and 50 mg/kg carbenoxolone, respectively. Carbenoxolone treatment dose-dependently improved fat mass, energy expenditure, the serum lipid profile, serum leptin and insulin and glucose tolerance. Furthermore, 50 mg/kg carbenoxolone reduced both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activity in the liver by 75% and 52%, respectively. These decreases were associated with increased glucokinase protein expression and activity in the liver. 4. Carbenoxolone inhibition of 11β-HSD1 in the liver, adipose and brain significantly improves the symptoms of metabolic syndrome in db/db mice. These improvements can be attributed to increased energy expenditure, decreased activity of the gluconeogenic enzymes PEPCK and G6Pase in the liver and improved glucokinase function in the liver and pancreas.

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“…Other companies, including Novartis, 116 Merck-Serono, 117,118 Sanofi-Aventis, 119 Schering-Plough 120 and in particular Abbott, [121][122][123][124][125][126][127][128] have also published work in this area but have not, to the best of our knowledge, progressed candidates to the clinic.…”

Section: Other Companies and Institutionsmentioning

confidence: 99%

Chapter 5. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development

Scott¹,

Chooramun²

2012

Drug Discovery

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Perhydroquinolylbenzamides as Novel Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1

Cited by 40 publications

References 61 publications

11β‐Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus

11β‐Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus

Inhibition of 11β‐hydroxysteroid dehydrogenase 1 by carbenoxolone affects glucose homeostasis and obesity in db/db mice

Chapter 5. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development

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