MK0916 - CAS 633317-53-0
Catalog number: 633317-53-0
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C18H19ClFN3
Molecular Weight:
331.82
COA:
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Description:
MK0916 is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. It is used for patients with type 2 diabetes mellitus and metabolic syndrome and obesity-related disorders. It produces mechanism-based activation of the hypothalamic-pituitary-adrenal axis and results in mean increases in adrenal androgen levels that remains within the normal range.
Purity:
98%
Appearance:
Solid powder
Synonyms:
3-[1-(4-Chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole anhydrate;3-[1-(4-Chlorophenyl)-3-fluorocyclobutyl]-4,5-dicyclopropyl-1,2,4-triazole;MK-0916;3-((1S,3S)-1-(4-chlorophenyl)-3-fluorocyclobutyl)-4,5-dicyclopropyl-4H-1,2,4
Solubility:
Soluble in DMSO, not in water
Storage:
-20°C Freezer
MSDS:
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Application:
MK0916 is used for patients with type 2 diabetes mellitus and metabolic syndrome and obesity-related disorders.
Quality Standard:
In-house standard
Quantity:
Milligrams-Grams
Boiling Point:
507.4±60.0 °C | Condition: Press: 760 Torr
Density:
1.52±0.1 g/cm3 | Condition: Temp: 20 °C Press: 760 Torr
InChIKey:
OGYZYOKAXYFLIU-UHFFFAOYSA-N
InChI:
InChI=1S/C18H19ClFN3/c19-13-5-3-12(4-6-13)18(9-14(20)10-18)17-22-21-16(11-1-2-11)23(17)15-7-8-15/h3-6,11,14-15H,1-2,7-10H2
Canonical SMILES:
C1CC1C2=NN=C(N2C3CC3)C4(CC(C4)F)C5=CC=C(C=C5)Cl
1.Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension.
Shah S;Hermanowski-Vosatka A;Gibson K;Ruck RA;Jia G;Zhang J;Hwang PM;Ryan NW;Langdon RB;Feig PU J Am Soc Hypertens. 2011 May-Jun;5(3):166-76. doi: 10.1016/j.jash.2011.01.009. Epub 2011 Mar 21.
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11β-HSD1 inhibitors, MK-0736 and MK-0916, in overweight-to-obese hypertensive patients. Patients aged 18-75 years with sitting diastolic blood pressure (SiDBP) 90-104 mm Hg, systolic BP <160 mm Hg (after washout of prior antihypertensive medications), and BMI ≥27 to <41 kg/m(2) were randomized to receive 2 or 7 mg/d MK-0736, 6 mg/d MK-0916, or placebo for 12 weeks (n = 51-54/group). Patients with BMI ≥20 to <27 kg/m(2) received 6 mg/d MK-0916 or placebo for 24 weeks (n = 19/group). The primary endpoint was placebo-adjusted change from baseline in trough SiDBP in patients treated for 12 weeks with 7 mg/d MK-0736. The primary endpoint was not met (placebo-adjusted reduction = 2.2 mm Hg; P = .157). With 7 mg/d MK-0736, placebo-adjusted LDL-C decreased by 12.3%, high-density lipoprotein cholesterol by 6.3%, and body weight by 1.4 kg. Both 11β-HSD1 inhibitors were generally well tolerated. In overweight-to-obese patients with hypertension, reduction in SiDBP with MK-0736 was not statistically significant.
2.11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors still improve metabolic phenotype in male 11β-HSD1 knockout mice suggesting off-target mechanisms.
Harno E;Cottrell EC;Yu A;DeSchoolmeester J;Gutierrez PM;Denn M;Swales JG;Goldberg FW;Bohlooly-Y M;Andersén H;Wild MJ;Turnbull AV;Leighton B;White A Endocrinology. 2013 Dec;154(12):4580-93. doi: 10.1210/en.2013-1613. Epub 2013 Oct 29.
The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)-fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11β-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11β-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting "off-target" mechanisms. Based on the patent literature, we synthesized another 11β-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses.
3.11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders?
Anagnostis P;Katsiki N;Adamidou F;Athyros VG;Karagiannis A;Kita M;Mikhailidis DP Metabolism. 2013 Jan;62(1):21-33. doi: 10.1016/j.metabol.2012.05.002. Epub 2012 May 30.
OBJECTIVE: ;Metabolic syndrome (MetS) and Cushing's syndrome share common features. It has been proposed that increased glucocorticoid activity at peripheral tissues may play a role in the pathogenesis of MetS and obesity-related disorders. It is well-known that intracellular cortisol concentrations are determined not only by plasma levels but also by the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the conversion of inactive cortisone to active cortisol, especially in the liver and adipose tissue. Another isoenzyme exists, the 11β-hydroxysteroid dehydrogenase type 2, which acts in the opposite direction inactivating cortisol to cortisone in the kidney. This review considers the significance of the 11β-HSD1 inhibition in the treatment of several features of MetS and provides current data about the development of 11β-HSD1 inhibitors, as new agents for this purpose.;MATERIALS/METHODS: ;Using PubMed, we searched for publications during the last 20years regarding the development of 11β-HSD1 inhibitors.;RESULTS: ;Emerging data from animal and human studies indicate an association of 11β-HSD1 over-expression with obesity and disorders in glucose and lipid metabolism.
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