The enzyme 11β–hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We ...report that pharmacologic inhibition of 11β-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11β-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11β-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11β-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.
Objective: Our main objective was to compare the regulation of cortisol production within omental (Om) and abdominal subcutaneous (Abd sc) human adipose tissue.
Methods and Procedures: Om and Abd sc ...adipose tissue were obtained at surgery from subjects with a wide range of BMI. Hydroxysteroid dehydrogenase (HSD) activity (3H‐cortisone and 3H‐cortisol interconversion) and expression were measured before and after organ culture with insulin and/or dexamethasone.
Results: Type 1 HSD (HSD1) mRNA and reductase activity were mainly expressed within adipocytes and tightly correlated with adipocyte size within both depots. There was no depot difference in HSD1 expression or reductase activity, while cortisol inactivation and HSD2 mRNA expression (expressed in stromal cells) were higher in Om suggesting higher cortisol turnover in this depot. Culture with insulin decreased HSD reductase activity in both depots. Culture with dexamethasone plus insulin compared to insulin alone increased HSD reductase activity only in the Om depot. This depot‐specific increase in reductase activity could not be explained by an alteration in HSD1 mRNA or protein, which was paradoxically decreased. However, in Om only, hexose‐6‐phosphate dehydrogenase (H6PDH) mRNA levels were increased by culture with dexamethasone plus insulin compared to insulin alone, suggesting that higher nicotinamide adenine dinucleotide phosphate‐oxidase (NADPH) production within the endoplasmic reticulum (ER) contributed to the higher HSD reductase activity.
Discussion: We conclude that in the presence of insulin, glucocorticoids cause a depot‐specific increase in the activation of cortisone within Om adipose tissue, and that this mechanism may contribute to adipocyte hypertrophy and visceral obesity.
The synthesis and biological activity of selective inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 are reported.
3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as inhibitors of ...11β-Hydroxysteroid Dehydrogenase Type 1 (HSD1). They were shown to be active in the mouse in vivo pharmacodynamic model (PD) for HSD1 but exhibited a potent off-target activation of the Pregnane X Receptor (PXR). SAR studies and synthesis of analogs that led to the discovery of a selective HSD1 inhibitor are described in detail.
The synthesis and biological activity of selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 are reported.
Adamantyl triazoles were identified as selective inhibitors of ...11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure–activity relationships of these inhibitors are presented.
Following the discovery of a metabolic ‘soft-spot’ on a bicyclo2.2.2octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. ...In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.
Following the discovery of a metabolic ‘soft-spot’ on a bicyclo2.2.2octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.
Heteroaryl substituted bicyclo2.2.2octyltriazoles have been shown to be potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) with excellent pharmacokinetic profiles. ...Compound
11 is a 2.2
nM inhibitor of human 11β-HSD1 enzyme.
Replacement of the pentyl chain on our original bicyclo2.2.2octyltriazole leads
1 and
2 has led to the discovery that heteroaryl substituted bicyclo2.2.2octyltriazoles are potent and selective 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) inhibitors with excellent pharmacokinetic profiles.
The 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes catalyze the interconversion of active glucocorticoids (GC) with their inert metabolites, thereby regulating the functional activity of GC. ...While 11β-HSD type 1 (11β-HSD1) activates GC from their 11-keto metabolites, 11β-HSD type 2 (11β-HSD2) inactivates GC. Here we report that both of these enzymes are expressed in human aortic smooth muscle cells (SMC), and that 11β-HSD1 is more abundant and is differentially regulated relative to 11β-HSD2. Stimulation of SMC with IL-1β or TNFα led to a time- and dose-dependent increase of mRNA levels for 11β-HSD1, while 11β-HSD2 mRNA levels decreased. Parallel enzyme activity studies showed increased conversion of
3H-cortisone to
3H-cortisol but not
3H-cortisol to
3H-cortisone, demonstrating 11β-HSD1 in SMC acts primarily as a reductase. A similar increase of 11β-HSD1 mRNA expression was also found in human bronchial SMC upon stimulation, indicating the regulatory effect is not limited to vascular smooth muscle. Additional parallel studies revealed a similar pattern of induction for 11β-HSD1 and monocyte chemoattractant protein-1, a well-defined proinflammatory molecule. These data suggest 11β-HSD1 may play an important role in regulating inflammatory responses in the artery wall and lung.
Macrophage migration inhibitory factor (MIF) is a cytokine that was first described as an inhibitor of the random migration of monocytes and macrophages and has since been proposed to have a number ...of immune and catalytic functions. One of the functions assigned to MIF is that of a tautomerase that interconverts the enol and keto forms of phenylpyruvate and (p-hydroxyphenyl)pyruvate and converts d-dopachrome, a stereoisomer of naturally occurring l-dopachrome, to 5,6-dihydroxyindole-2-carboxylic acid. The physiological significance of the MIF enzymatic activity is unclear. The three-dimensional structure of MIF is strikingly similar to that of two microbial enzymes (4-oxalocrotonate tautomerase and 5-carboxymethyl-2-hydroxymuconate isomerase) that otherwise share little sequence identity with MIF. MIF and these two enzymes have an invariant N-terminal proline that serves as a catalytic base. Here we report a new biological function for MIF, as an inhibitor of monocyte chemoattractant protein 1- (MCP-1-) induced chemotaxis of human peripheral blood monocytes. We find that MIF inhibition of chemotaxis does not occur at the level of the CC chemokine receptor for MCP-1, CCR2, since MIF does not alter the binding of 125I-MCP-1 to monocytes. The role of MIF enzymatic activity in inhibition of monocyte chemotaxis and random migration was studied with two MIF mutants in which the N-terminal proline was replaced with either a serine or a phenylalanine. Both mutants remain capable of inhibiting monocyte chemotaxis and random migration despite significantly reduced or no phenylpyruvate tautomerase activity. These data suggest that this enzymatic activity of MIF does not play a role in its migration inhibiting properties.
3-Aryl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). They are active in both in vitro and an in vivo mouse pharmacodynamic ...(PD) model. The synthesis and structure activity relationships are presented.
The enzyme 11 beta -hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We ...report that pharmacologic inhibition of 11 beta -HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11 beta -HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11 beta -HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11 beta -HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.
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