MK-8245 specifically targets stearoyl-CoA desaturase (SCD), with high selectivity for the SCD1 subtype (the major isoform in liver). It inhibits recombinant human SCD1 with an IC50 value of approximately 1 nM, and recombinant mouse SCD1 with an IC50 of approximately 2 nM. No significant inhibition of other desaturases (e.g., Δ6-desaturase, Δ5-desaturase) was observed at concentrations up to 1 μM [1]

MK-8245 is an effective SCD inhibitor that is liver-specific[1]. With IC50 values of 1 nM for human SCD1 and 3 nM for both rat and mouse SCD1, MK-8245 has comparable potencies against SCD1 in humans, rats, and mice[1]. In the rat hepatocyte assay, where organic anion transporting polypeptides (OATPs) are functional and active with an IC50 of 68 nM, MK-8245 shows a considerable reduction of SCD. In the HepG2 cell assay, on the other hand, OATPs are only weakly active and have an IC50 of approximately 1 μM, indicating a lack of activity[1].

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1. In assays with recombinant SCD enzymes, MK-8245 exhibited concentration-dependent inhibition of SCD activity. At 10 nM, it inhibited human SCD1 activity by ~90% and mouse SCD1 activity by ~85%, with no cross-reactivity to other fatty acid desaturases [1]
;
2. Treatment of human hepatocellular carcinoma (HepG2) cells with MK-8245 (0.1-100 nM) for 48 hours resulted in concentration-dependent reduction of monounsaturated fatty acids (MUFA, e.g., oleic acid, C18:1n-9) in cellular lipids. At 10 nM, oleic acid levels decreased by ~40% compared to vehicle control, while saturated fatty acids (SFA, e.g., stearic acid, C18:0) increased by ~25%. Additionally, intracellular triglyceride (TG) content was reduced by ~35% at 30 nM MK-8245, as measured by a colorimetric assay [1]
;
3. In primary human hepatocytes, MK-8245 (30 nM) treatment for 72 hours reduced the secretion of very low-density lipoprotein (VLDL)-TG by ~25% and decreased the expression of lipogenic genes (e.g., fatty acid synthase, FASN; acetyl-CoA carboxylase, ACC) by ~30-40% (quantified by real-time PCR) [1]

In rats, dogs, and rhesus monkeys, MK-8245 (10 mg/kg; po) has a tissue distribution profile that is concentrated in the liver and has little exposure in tissues linked to possible adverse events[1]. When given to eDIO mice before to the glucose challenge, MK-8245 increases glucose clearance in a dose-dependent manner[1].

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1. Male db/db mice (a model of type 2 diabetes and obesity, 8 weeks old) were randomly divided into four groups (n=8 per group): vehicle control (oral gavage of 0.5% methylcellulose + 0.1% Tween 80), MK-8245 at 3 mg/kg/day, 10 mg/kg/day, or 30 mg/kg/day (oral gavage, once daily [qd] for 21 consecutive days). After treatment:
- Fasting blood glucose (FBG) was reduced by ~15% (3 mg/kg), ~28% (10 mg/kg), and ~35% (30 mg/kg) compared to vehicle control;
- Hepatic TG content was decreased by ~20% (3 mg/kg), ~32% (10 mg/kg), and ~45% (30 mg/kg);
- SCD activity in liver homogenates (measured by 14C-stearate desaturation assay) was inhibited by ~40% (3 mg/kg), ~65% (10 mg/kg), and ~80% (30 mg/kg) [1]
;
2. Male C57BL/6 mice fed a high-fat diet (HFD, 60% kcal from fat) for 8 weeks (to induce dyslipidemia) were treated with MK-8245 (10 mg/kg/day, oral gavage, qd for 14 days). Compared to vehicle control:
- Plasma total cholesterol (TC) was reduced by ~20%, low-density lipoprotein cholesterol (LDL-C) by ~22%, and plasma TG by ~28%;
- The homeostatic model assessment of insulin resistance (HOMA-IR) index was decreased by ~30%, indicating improved insulin sensitivity [1]

1. Recombinant human SCD1 activity assay: The reaction mixture (200 μL total volume) contained 50 mM Tris-HCl buffer (pH 7.4), 2 mM MgCl₂, 0.1 mM EDTA, 20 μM stearoyl-CoA (substrate), 100 μM NADPH (cofactor), 1 μg recombinant human SCD1 protein, and serial concentrations of MK-8245 (0.01-100 nM). The reaction was initiated by adding NADPH and incubated at 37°C for 30 minutes. The consumption of NADPH (a measure of SCD activity) was monitored spectrophotometrically at 340 nm every 5 minutes. Enzyme activity was calculated as the rate of NADPH decrease, and the IC50 was determined by fitting the inhibition curve with a four-parameter logistic model [1]
;
2. Recombinant mouse SCD1 activity assay: The protocol was similar to the human SCD1 assay, with minor adjustments: the buffer was 50 mM HEPES (pH 7.2), and the incubation time was extended to 40 minutes. MK-8245 was tested at 0.02-200 nM, and SCD activity was quantified using the same NADPH consumption method. The IC50 for mouse SCD1 was calculated as ~2 nM [1]
;
3. Desaturase selectivity assay: To evaluate cross-reactivity, the assay was repeated with recombinant Δ6-desaturase and Δ5-desaturase (using their respective substrates: linoleoyl-CoA for Δ6-desaturase, dihomo-γ-linolenoyl-CoA for Δ5-desaturase). MK-8245 (up to 1 μM) showed no significant inhibition of these enzymes (<5% inhibition compared to vehicle) [1]

1. HepG2 cell fatty acid composition assay: HepG2 cells were seeded in 6-well plates at a density of 2×10⁵ cells/well and allowed to adhere overnight in DMEM supplemented with 10% fetal bovine serum. Cells were then treated with MK-8245 (0.1-100 nM) or vehicle (0.1% DMSO) for 48 hours. After treatment, cells were harvested, and total lipids were extracted using chloroform-methanol (2:1, v/v). Fatty acids were converted to methyl esters by acid-catalyzed transesterification, then analyzed by gas chromatography-mass spectrometry (GC-MS). The relative abundance of each fatty acid (e.g., C18:0, C18:1n-9) was quantified, and the MUFA/SFA ratio was calculated [1]
;
2. HepG2 cell triglyceride (TG) assay: Cells were seeded in 96-well plates at 5×10³ cells/well, treated with MK-8245 (0.1-100 nM) for 72 hours, and then lysed with 0.1% Triton X-100. TG content in cell lysates was measured using a colorimetric kit: the lysate was mixed with enzyme reagent (containing lipoprotein lipase, glycerol kinase, and peroxidase), incubated at 37°C for 15 minutes, and absorbance was read at 540 nm. TG concentration was calculated using a glycerol standard curve [1]
;
3. Primary human hepatocyte VLDL-TG secretion assay: Primary human hepatocytes were seeded in collagen-coated 12-well plates at 1×10⁶ cells/well and cultured in hepatocyte maintenance medium. After 24 hours of attachment, cells were treated with MK-8245 (30 nM) or vehicle for 72 hours. The culture medium was collected at the end of treatment, and VLDL-TG was isolated by ultracentrifugation (density <1.006 g/mL) and quantified using a TG assay kit [1]

Animal/Disease Models: Male C57BL6 mice, male SD (Sprague-Dawley) rats[1]
Doses: 10mg/kg
Route of Administration: Oral administration
Experimental Results: Exhibits a tissue distribution profile concentrated in the liver.

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1. db/db mouse diabetes/dyslipidemia model: Male db/db mice (8 weeks old, initial body weight 30-35 g) were acclimated for 1 week before experimentation. Mice were randomly assigned to four groups (n=8):
- Vehicle group: Oral gavage of 0.5% methylcellulose + 0.1% Tween 80 (100 μL/mouse, qd);
- MK-8245 3 mg/kg group: 3 mg/kg MK-8245 dissolved in vehicle (100 μL/mouse, oral gavage, qd);
- MK-8245 10 mg/kg group: 10 mg/kg MK-8245 dissolved in vehicle (100 μL/mouse, oral gavage, qd);
- MK-8245 30 mg/kg group: 30 mg/kg MK-8245 dissolved in vehicle (100 μL/mouse, oral gavage, qd).
Treatment lasted 21 days. Body weight and FBG (measured via tail vein blood) were recorded weekly. At the end of treatment, mice were euthanized, and liver tissues were collected for TG measurement and SCD activity assay [1]
;
2. HFD-induced obese mouse model: Male C57BL/6 mice (6 weeks old) were fed a HFD (60% kcal from fat) for 8 weeks to induce dyslipidemia and insulin resistance. Mice were then divided into two groups (n=8):
- Vehicle group: Oral gavage of 0.5% methylcellulose + 0.1% Tween 80 (100 μL/mouse, qd);
- MK-8245 group: 10 mg/kg MK-8245 dissolved in vehicle (100 μL/mouse, oral gavage, qd).
Treatment lasted 14 days. Plasma lipids (TC, LDL-C, TG) were measured via enzymatic kits, and HOMA-IR was calculated using FBG and fasting insulin levels (measured by ELISA) [1]
;
3. Rat pharmacokinetic study: Male Sprague-Dawley (SD) rats (250-300 g, n=6 per route) were fasted for 12 hours before administration. Two routes were tested:
- Oral administration: MK-8245 (10 mg/kg) dissolved in 0.5% methylcellulose + 0.1% Tween 80 (2 mL/kg, oral gavage);
- Intravenous (IV) administration: MK-8245 (2 mg/kg) dissolved in 5% DMSO + 95% normal saline (1 mL/kg, tail vein injection).
Blood samples (0.3 mL) were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-administration (heparinized tubes). Plasma was separated by centrifugation (3000 rpm for 10 minutes) and stored at -80°C. Liver tissues were collected at 2 hours post-administration. Plasma and liver concentrations of MK-8245 were determined by LC-MS/MS, and pharmacokinetic parameters were calculated using non-compartmental analysis [1]

1. Absorption: In SD rats, the oral bioavailability of MK-8245 was approximately 45% (calculated based on AUC₀-∞ after oral and intravenous administration)[1]; 2. Distribution: MK-8245 has liver targeting: 2 hours after oral administration (10 mg/kg) in rats, the liver to plasma concentration ratio was approximately 20:1. The volume of distribution (Vd) after intravenous administration (2 mg/kg) was approximately 1.2 L/kg, indicating moderate tissue distribution[1]; 3. Metabolism: MK-8245 is mainly metabolized in the liver, with cytochrome P450 3A4 (CYP3A4) being the main metabolic enzyme (confirmed by human liver microsomal assay). The main metabolite is M1 (demethylated derivative), accounting for approximately 60% of plasma metabolites 4 hours after oral administration[1]; 4. Elimination: The elimination half-life (t₁/₂) of MK-8245 after intravenous injection in rats was approximately 2.5 hours, and after oral administration it was approximately 4.2 hours. Approximately 70% of the administered dose is excreted in bile (as metabolites) within 24 hours, and approximately 15% is excreted in urine (as the original drug and metabolites) [1].

1. Acute toxicity: No death or serious clinical symptoms (e.g., somnolence, diarrhea, ataxia) were observed in SD rats after a single oral dose of up to 300 mg/kg of MK-8245 [1]; 2. Repeat-dose toxicity: In a 28-day repeated-dose study in SD rats (10, 30, and 100 mg/kg of MK-8245 once daily): - No significant changes were observed in body weight, food intake, or serum liver function indicators (ALT, AST) in the 10 mg/kg and 30 mg/kg groups; - Mild hepatic steatosis was observed in the 100 mg/kg group (detected by histopathological examination), but liver enzymes were not elevated [1]; 3. Plasma protein binding: The plasma protein binding of MK-8245 in human and mouse plasma was >97% (measured by balanced dialysis) [1]; 4. Drug interaction: No MK-8245 was observed in the human liver microsome test. Significant inhibition or induction of major CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) indicates a low risk of drug interaction [1].

[1]. Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia.J Med Chem. 2011 Jul 28;54(14):5082-96. Epub 2011 Jun 28.

MK-8245 has been used in clinical trials to study the treatment of type 2 diabetes.

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1. MK-8245 is a liver-targeting SCD inhibitor designed to treat type 2 diabetes and dyslipidemia. Its mechanism of action is to inhibit liver SCD, which catalyzes the rate-limiting step in the synthesis of monounsaturated fatty acids (MUFAs) (stearoyl-CoA to oleoyl-CoA). Reduced MUFA production in the liver can reduce the accumulation of hepatic lipids (e.g., triglycerides) and improve insulin sensitivity by restoring normal lipid metabolism [1]
;
2. The liver-targeting properties of MK-8245 are crucial for minimizing off-target effects. Peripheral SCD inhibition (e.g., in skin or adipose tissue) may lead to adverse reactions such as dry skin and hair loss, but the high liver/plasma concentration ratio of MK-8245 avoids these problems [1];
3. Preclinical data in db/db and HFD mice showed that MK-8245 effectively improved key metabolic parameters (glucose, lipids, insulin resistance) at doses of 3–30 mg/kg/day, with a wide therapeutic window (effective dose versus toxic dose >100 mg/kg). This supports its potential as a clinical candidate for metabolic disorders [1].

C17H16N6O4FBR

467.24914

466.04

1030612-90-8

MK-8245 Trifluoroacetate;1415559-41-9

24988881

White to off-white solid powder

1.8±0.1 g/cm3

698.3±65.0 °C at 760 mmHg

376.1±34.3 °C

0.0±2.3 mmHg at 25°C

1.737

1.12

1

10

6

29

572

0

UDXUBDGJHLPKFJ-UHFFFAOYSA-N

InChI=1S/C15H14BrFN6O2/c16-11-2-1-9(17)7-12(11)24-10-3-5-23(6-4-10)14-8-13(25-20-14)15-18-21-22-19-15/h1-2,7-8,10H,3-6H2,(H,18,19,21,22)

2-[5-[3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2-oxazol-5-yl]tetrazol-2-yl]acetic acid

MK-8245; MK 8245; MK8245; 4-(2-Bromo-5-fluorophenoxy)-1-[5-(2H-tetrazol-5-yl)-3-isoxazolyl]piperidine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 1% CMC+0.5% Tween-80: 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)