Is 11β-hydroxysteroid dehydrogenase type 1 a good therapeutic target for blockade of glucocorticoid actions?

Chrousos, George P.

doi:10.1073/pnas.0401671101

Cited by 36 publications

(15 citation statements)

References 17 publications

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“…Recent studies have shown that inhibition of 11β-HSD1 activity helps to reverse metabolic pathological conditions such as T2DM [38]. ROD treatment resulted in ∼4-fold increase in 11β-HSD1 content in epididymal fat compared to controls (p<0.05, Figure 5).…”

Section: Resultsmentioning

confidence: 94%

Effects of Selective and Non-Selective Glucocorticoid Receptor II Antagonists on Rapid-Onset Diabetes in Young Rats

et al. 2014

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The blockade of glucocorticoid (GC) action through antagonism of the glucocorticoid receptor II (GRII) has been used to minimize the undesirable effects of chronically elevated GC levels. Mifepristone (RU486) is known to competitively block GRII action, but not exclusively, as it antagonizes the progesterone receptor. A number of new selective GRII antagonists have been developed, but limited testing has been completed in animal models of overt type 2 diabetes mellitus. Therefore, two selective GRII antagonists (C113176 and C108297) were tested to determine their effects in our model of GC-induced rapid-onset diabetes (ROD). Male Sprague-Dawley rats (∼ six weeks of age) were placed on a high-fat diet (60%), surgically implanted with pellets containing corticosterone (CORT) or wax (control) and divided into five treatment groups. Each group was treated with either a GRII antagonist or vehicle for 14 days after surgery: CORT pellets (400 mg/rat) + antagonists (80 mg/kg/day); CORT pellets + drug vehicle; and wax pellets (control) + drug vehicle. After 10 days of CORT treatment, body mass gain was increased with RU486 (by ∼20% from baseline) and maintained with C113176 administration, whereas rats given C108297 had similar body mass loss (∼15%) to ROD animals. Fasting glycemia was elevated in the ROD animals (>20 mM), normalized completely in animals treated with RU486 (6.2±0.1 mM, p<0.05) and improved in animals treated with C108297 and C113176 (14.0±1.6 and 8.8±1.6 mM, p<0.05 respectively). Glucose intolerance was normalized with RU486 treatment, whereas acute insulin response was improved with RU486 and C113176 treatment. Also, peripheral insulin resistance was attenuated with C113176 treatment along with improved levels of β-cell function while C108297 antagonism only provided modest improvements. In summary, C113176 is an effective agent that minimized some GC-induced detrimental metabolic effects and may provide an alternative to the effective, but non-selective, GRII antagonist RU486.

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Section: Resultsmentioning

confidence: 94%

Effects of Selective and Non-Selective Glucocorticoid Receptor II Antagonists on Rapid-Onset Diabetes in Young Rats

et al. 2014

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“…This may lead to a compensatory activation of the HPA axis that would try to correct for the perceived glucocorticoid deficit throughout the body (15). The HPA over activation may result, in addition to the necessary extra cortisol, in excess mineralocorticoid precursors, such as corticosterone and deoxycorticosterone, and excess adrenal androgens, such as DHEA-s and 4-androstenedione.…”

Section: Discussionmentioning

confidence: 97%

Modulation of 11β-Hydroxysteroid Dehydrogenase (11βHSD) Activity Biomarkers and Pharmacokinetics of PF-00915275, a Selective 11βHSD1 Inhibitor

Courtney

Stewart

Toh

et al. 2008

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…It converts the inactive glucocorticoid cortisone into the active hormone cortisol within cells, and through this local action it increases intracellular glucocorticoid activity in the liver and other organs ( Figure 1) [2,5,6]. It is a working hypothesis that inhibition of 11b-HSD1 in patients with the metabolic syndrome will reduce intracellular cortisol concentrations and lead to improvement in one or more of its components [1,7,8]. Some 11b-HSD1 inhibitors have entered into clinical testing; included among these are the compounds AMG221 [9], INCB13739 [10], MK-0916 [11,12] and MK-0736 [12].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

Wright

Stone

Crumley

et al. 2013

Brit J Clinical Pharma

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AIMSTo characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. METHODSData are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4-100 mg MK-0916 (n = 16). In the second study, subjects received 0.2-225 mg MK-0916 followed by daily doses of 0.2-100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [13 C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [ 13 C4]cortisone. RESULTSDoses Ն3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1-1.8 h). Exposure (measured as the area under the concentration-time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nM and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11b-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nM. Exposure to MK-0916 was generally well tolerated. CONCLUSIONSThese findings indicate that 11b-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The intracellular enzyme 11b-hydroxysteroid dehydrogenase type 1 converts the inactive glucocorticoid cortisone into the active hormone cortisol in many tissues, including the liver and adipocytes. It is thought that increased conversion of cortisone to cortisol contributes to pathophysiology associated with the metabolic syndrome.• MK-0916 is an inhibitor of 11b-hydroxysteroid dehydrogenase type 1 that has been evaluated clinically as a potential therapy for type 2 diabetes, obesity or hypertension. WHAT THIS STUDY ADDS• In lean, healthy male subjects, MK-0916 was well tolerated when given in oral doses that were sufficient to provide profound inhibition of hepatic conversion of cortisone to cortisol.• Multiple-dose administration of 6 mg day -1 MK-0916 provided mean plasma concentrations >200 nM at all times, a plasma drug concentration that inhibited systemic 11b-hydroxysteroid dehydrogenase type 1 by 84%.

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Is 11β-hydroxysteroid dehydrogenase type 1 a good therapeutic target for blockade of glucocorticoid actions?

Cited by 36 publications

References 17 publications

Effects of Selective and Non-Selective Glucocorticoid Receptor II Antagonists on Rapid-Onset Diabetes in Young Rats

Effects of Selective and Non-Selective Glucocorticoid Receptor II Antagonists on Rapid-Onset Diabetes in Young Rats

Modulation of 11β-Hydroxysteroid Dehydrogenase (11βHSD) Activity Biomarkers and Pharmacokinetics of PF-00915275, a Selective 11βHSD1 Inhibitor

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

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