Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension

Shah, Sukrut; Hermanowski‐Vosatka, Anne; Gibson, Kendra; Ruck, Rae Ann; Jia, Gang; Zhang, Junyi; Hwang, Peggy; Ryan, Nicholas; Langdon, Ronald B.; Feig, Peter U.

doi:10.1016/j.jash.2011.01.009

Cited by 87 publications

(108 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Both drugs had modest effects on ambulatory blood pressure during the daytime (6 mg MK-0916: systolic −3.8 and diastolic −3.1 mmHg; 7 mg MK-0736: systolic −6.0 and diastolic −1.8 mmHg). Notably, in this trial MK-0916 did not increase cholesterol levels [88].…”

Section: βHsd1 Inhibitorsmentioning

confidence: 54%

“…A number of selective 11βHSD1 inhibitors have been tested in humans, and data from phase II clinical trials have been published to date on four of them (MK-0916, MK-0736, INCB-13739 and ABT-384) [88][89][90][91]; for a summary on metabolic outcomes see Table 1. In obese patients with type 2 diabetes, 6 mg MK-0916 daily for 12 weeks lowered HbA 1c by 0.3% but there was no effect on fasting plasma glucose (FPG, the primary endpoint).…”

Section: βHsd1 Inhibitorsmentioning

confidence: 99%

“…INCB-13739 has impressively potent effects to inhibit 11βHSD1 in vivo, including in adipose tissue. The antihypertensive effects of MK-0916 and MK-0736 have been studied further in normal weight and obese hypertensive patients without other anti-hypertensive medications [88]. Seven milligrams MK-0736 did not lower sitting diastolic blood pressure (primary endpoint) but had a small effect on sitting systolic blood pressure (−4.2 mmHg) whereas 6 mg MK-0916 lowered sitting diastolic blood pressure (−3.1 mmHg) but had no effect on sitting systolic blood pressure.…”

Section: βHsd1 Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

et al. 2014

View full text Add to dashboard Cite

Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesityassociated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoidregenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissuespecific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.

show abstract

Section: βHsd1 Inhibitorsmentioning

confidence: 54%

Section: βHsd1 Inhibitorsmentioning

confidence: 99%

Section: βHsd1 Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Shah és munkatársai a szelektív 11-β-HSD-1-gátló MK-0736 és MK-0916 vizsgálatával igazolták, hogy elhízott hypertoniás betegekben az MK-0736 hatására a placebóhoz képest szignifi kánsan csökkent az LDL-és HDL-koleszterin-szint, valamint a testtömeg [48].…”

Section: Klinikai Vizsgálatokban Kipróbált 11-β-hsd-1-gátlókunclassified

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

et al. 2013

View full text Add to dashboard Cite

A glükokortikoidok szabályozzák a szénhidrát-és aminosav-anyagcserét, modulálják az immunrendszer működé-sét és a stresszre adott válaszreakciókat. Elégtelen, illetve fokozott szekréciójuk jellegzetes kórképeket okoz. A szervezet glükokortikoidhormon-ellátottsága mellett az utóbbi évtizedben előtérbe került az adott szövetekben loká-lisan képződő glükokortikoidok patofi ziológiai szerepének kutatása. A lokális glükokortikoidellátottság egyik kulcsenzime a sejtek endoplazmatikus reticulumában elhelyezkedő 11-β-hidroxi-szteroid-dehidrogenáz enzim 1-es és 2-es típusa, amelyek az inaktív kortizon és az aktív kortizol közötti kétirányú átalakulást katalizálják. Az 1-es tí-pusú enzim elsősorban a kortizon aktiválásában játszik szerepet és főként a májban, gonádokban, zsírszövetben, agyban és csontban a biológiailag aktív kortizol lokális képződéséért felelős. Az enzimet kódoló gén az 1-es kromoszómán található. A szerzők jelen munkájukban összefoglalják a 11-β-hidroxi-szteroid-dehidrogenáz enzim 1-es típusának működésével kapcsolatba hozható klinikai és (kór)élettani folyamatokat. Összefoglalójukban áttekintik az enzimaktivitás gátlásában szerepet játszó genetikai variánsokkal kapcsolatos legfontosabb ismereteket és az enzimaktivitást gátló vegyületekkel szerzett tapasztalatokat. Az eredmények összegzéséből kitűnik, hogy bár ismereteink sok területen még hiányosak, az 1-es típusú enzim működésének és/vagy termelődésének gyógyszeres befolyásolása ígéretes terápiás lehetőséget jelenthet elhízásban, csontritkulásban vagy akár cukorbetegségben szenvedő betegek kezelésében. Orv. Hetil., 2013, 154, 283-293. Kulcsszavak: kortizol, kortizon, szövetspecifi kus glükokortikoidhatás, 11-β-hidroxi-szteroid-dehidrogenáz 1-es típus Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disordersGlucocorticoids play an important role in the regulation of carbohydrate and amino acid metabolism, they modulate the function of the immune system, and contribute to stress response. Increased and decreased production of glucocorticoids causes specifi c diseases. In addition to systemic hypo-or hypercortisolism, alteration of local synthesis and metabolism of cortisol may result in tissue-specifi c hypo-or hypercortisolism. One of the key enzymes participating in the local synthesis and metabolism of cortisol is the 11β-hydroxysteroid dehydrogenase enzyme. Two isoforms, type 1 and type 2 enzymes are located in the endoplasmic reticulum and catalyze the interconversion of hormonally active cortisol and inactive cortisone. The type 1 enzyme mainly works as an activator, and it is responsible for the generation of cortisol from cortisone in liver, adipose tissue, brain and bone. The gene encoding this enzyme is located on chromosome 1. The authors review the physiological and pathophysiological processes related to the function of the type 1 11β-hydroxysteroid dehydrogenase enzyme. They summarize the potential signifi cance of polymorphic variants of the enzyme in clinical diseases as well as knowledge related to inhibitors of...

show abstract

“…Inhibition of this enzyme may prevent conversion of the biologically inactive cortisone into active cortisol locally into different tissues including the adipose tissue. Preclinical and clinical studies suggest a modest positive effect on metabolic parameters (29)(30)(31)(32), but further studies are needed to conclude on whether the 11b-HSD1 inhibitors could also reduce the risk for developing comorbid depression.…”

mentioning

confidence: 99%

‘Let food be thy medicine, and medicine be thy food’: Hippocrates revisited

Wegener¹

2014

Acta Neuropsychiatr.

View full text Add to dashboard Cite

Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension

Cited by 87 publications

References 17 publications

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

‘Let food be thy medicine, and medicine be thy food’: Hippocrates revisited

Contact Info

Product

Resources

About