MK-8245

Catalog No.S1158

MK-8245 is an liver-targeting inhibitor of stearoyl-CoA desaturase (SCD) with IC50 of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1, with anti-diabetic and anti-dyslipidemic efficacy. Phase 2.

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MK-8245 Chemical Structure

MK-8245 Chemical Structure
Molecular Weight: 467.25

Validation & Quality Control

Quality Control & MSDS

Related Compound Libraries

MK-8245 is available in the following compound libraries:

Product Information

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Product Description

Biological Activity

Description MK-8245 is an liver-targeting inhibitor of stearoyl-CoA desaturase (SCD) with IC50 of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1, with anti-diabetic and anti-dyslipidemic efficacy. Phase 2.
Targets SCD1 (human) [1] SCD1 (rat) [1] SCD1 (mouse) [1]
IC50 1 nM 3 nM 3 nM
In vitro MK-8245, a phenoxy piperidine isoxazole derivative, has been identified as a potent and liver-specific SCD inhibitor. It contains a tetrazole acetic acid moiety, which is the key molecule for OATPs recognition and liver-targeting. MK-8245 displays similar potencies against human, rat and mouse SCD1 with IC50 values of 1 nM for human SCD1 and 3 nM for both rat SCD1 and mouse SCD1. MK-8245 exhibits a significant SCD inhibition in the rat hepatocyte assay which contains functional, active OATPs with IC50 of 68 nM, while being only weakly active in the HepG2 cell assay which is devoid of active OATPs with IC50 of ~1 μM. MK-8245 displays highly selective activity for the Δ-5 and Δ-6 desaturases (i.e., >100000 μM vs rat and human Δ5D and Δ6D as assessed in the HepG assay. [1]
In vivo Administration of MK-8245 at 10 mg/kg in mice exhibits a tissue distribution profile concentrated in the liver. It shows a liver-to-Harderian gland ratio of 21, suggesting a high degree of liver-targeting compared to a systemically distributed compound with liver-to-Harderian gland ratio of 1.5. Oral dosing of MK-8245 in mice, rats, dogs, and rhesus monkeys demonstrates that MK-8245 is distributed mainly to the liver, with low exposure in tissues associated with potential adverse events. The liver-to-skin ratios are >30:1 in all four species. Administration of MK-8245 to eDIO mice before the glucose challenge improves glucose clearance in a dose-dependent manner with ED50 of 7 mg/kg. [1]
Features A potent hepatic SCD inhibitor, and does not affect SCD enzyme in skin and eye tissues like other systemically distributed SCD inhibitors.

Protocol(Only for Reference)

Kinase Assay: [1]

SCD1 enzyme activity assay The potency of MK-8245 against the stearoyl-CoA desaturase is determined by measuring the conversion of radiolabeled stearoyl-CoA to oleoyl-CoA using rat liver microsome or human SCDl (hSCD-1). Liver microsome is prepared from male Wistar or Spraque Dawley rats on a high carbohydrate diet for 3 days. The livers are homogenized (1 :10 w/v) in a buffer containing 250 mM sucrose, 1 mM EDTA, 5 mM DTT and 50 mM Tris-HCl (pH 7.5). After a 100,000 x g centrifugation for 60 minutes, the liver microsome pellet is suspended in a buffer containing 100 mM sodium phosphate, 20% glycerol, 2 mM DTT and stored at -78 °C. The human SCDl desaturase system is reconstituted using human SCDl from a baculovirus/Sf9 expression system, cytochrome B5 and cytochrome B5 reductase. Typically, different concentrations of MK-8245 in 2 μL DMSO is incubated for 15 minutes at room temperature with 180 μL of the SCD enzyme in a buffer containing 100 mM Tris-HCl (pH 7.5), ATP (5 mM), Coenzyme-A (0.1 mM), Triton X-100 (0.5 mM) and NADH (2 mM). The reaction is initiated by the addition of 20 μL of [3H]-stearoyl-CoA (final concentration = 2 μM, radioactivity concentration = 1 μCi/mL). After 10 minutes, the reaction mixture (80 μL) is mixed with a calcium chloride/charcoal aqueous suspension (100 μL charcoal (10% w/v) plus 25 μL CaCl2 (2N). After centrifugation to precipitate the radioactive fatty acid species, tritiated water released from 9,10-[3H]-stearoyl-CoA by the SCD enzyme is quantified on a scintillation counter.

Animal Study: [1]

Animal Models Male C57/Bl6 mice
Formulation Suspended in 1% methocel in saline
Dosages ~30 mg/kg
Administration Orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Oballa RM, et al. J Med Chem, 2011, 54(14), 5082-5096.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00972322 Completed Type 2 Diabetes Mellitus Merck Sharp & Dohme Corp. August 2009 Phase 1
NCT00846391 Terminated Type 2 Diabetes Mellitus Merck Sharp & Dohme Corp. December 2008 Phase 2
NCT00790556 Completed Type 2 Diabetes Merck Sharp & Dohme Corp. October 2008 Phase 1

Chemical Information

Download MK-8245 SDF
Molecular Weight (MW) 467.25
Formula

C17H16BrFN6O4

CAS No. 1030612-90-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 93 mg/mL (199.03 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% CMC+0.5% Tween-80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 2-(5-(3-(4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)isoxazol-5-yl)-2H-tetrazol-2-yl)acetic acid

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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