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 是一种有效的肝脏特异性 SCD 抑制剂[1]。 MK-8245 对人类 SCD1 的 IC50 值为 1 nM，对大鼠和小鼠 SCD1 的 IC50 值为 3 nM，因此在人类、大鼠和小鼠中具有相当的抗 SCD1 效力[1]。在大鼠肝细胞测定中，有机阴离子转运多肽 (OATP) 具有功能性和活性，IC50 为 68 nM，MK-8245 显示 SCD 显着降低。另一方面，在 HepG2 细胞测定中，OATP 仅具有微弱活性，IC50 约为 1 μM，表明缺乏活性[1]。

在大鼠、狗和恒河猴中，MK-8245（10 mg/kg；口服）的组织分布特征集中在肝脏中，在与可能的不良事件相关的组织中几乎没有暴露[1]。当在葡萄糖激发前给予 eDIO 小鼠时，MK-8245 以剂量依赖性方式增加葡萄糖清除率[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 from AUC₀-∞ after oral and IV administration) [1]
;
2. Distribution: MK-8245 showed liver-targeting properties: at 2 hours post-oral administration (10 mg/kg) in rats, the liver-to-plasma concentration ratio was ~20:1. The volume of distribution (Vd) after IV administration (2 mg/kg) was ~1.2 L/kg, indicating moderate tissue distribution [1]
;
3. Metabolism: MK-8245 was primarily metabolized in the liver, with cytochrome P450 3A4 (CYP3A4) as the major metabolizing enzyme (confirmed by human liver microsome assays). The main metabolite was M1 (demethylated derivative), accounting for ~60% of plasma metabolites at 4 hours post-oral administration [1]
;
4. Elimination: The elimination half-life (t₁/₂) of MK-8245 in rats was ~2.5 hours after IV administration and ~4.2 hours after oral administration. Approximately 70% of the administered dose was excreted in bile (as metabolites) within 24 hours, and ~15% was excreted in urine (as unchanged drug and metabolites) [1]

1. Acute toxicity: No mortality or severe clinical signs (e.g., lethargy, diarrhea, ataxia) were observed in SD rats after a single oral dose of MK-8245 up to 300 mg/kg [1]
;
2. Repeat-dose toxicity: In a 28-day repeat-dose study in SD rats (oral administration of 10, 30, 100 mg/kg/day MK-8245, qd):
- No significant changes in body weight, food intake, or serum liver function markers (ALT, AST) were observed in the 10 and 30 mg/kg groups;
- The 100 mg/kg group showed mild hepatic steatosis (detected by histopathological examination) but no elevation of liver enzymes [1]
;
3. Plasma protein binding: The plasma protein binding rate of MK-8245 was >97% in both human and rat plasma (measured by equilibrium dialysis) [1]
;
4. Drug-drug interaction: No significant inhibition or induction of major CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) by MK-8245 was observed in human liver microsome assays, indicating a low risk of drug-drug interactions [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 trials studying the treatment of Type 2 Diabetes Mellitus.

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1. MK-8245 is a liver-targeted SCD inhibitor designed to treat type 2 diabetes and dyslipidemia. Its mechanism of action is based on inhibiting hepatic SCD, which catalyzes the rate-limiting step in MUFA synthesis (conversion of stearoyl-CoA to oleoyl-CoA). Reduced MUFA production in the liver decreases hepatic lipid accumulation (e.g., TG) and improves insulin sensitivity by restoring normal lipid metabolism [1]
;
2. The liver-targeting property of MK-8245 is critical for minimizing off-target effects. Peripheral SCD inhibition (e.g., in skin or adipose tissue) can cause adverse effects such as skin dryness and hair loss, but MK-8245’s high liver/plasma concentration ratio avoids these issues [1]
;
3. Preclinical data in db/db and HFD mice demonstrate that MK-8245 effectively improves key metabolic parameters (glucose, lipids, insulin resistance) at doses of 3-30 mg/kg/day, with a wide therapeutic window (effective doses vs. 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

119.4

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.35 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.35 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.35 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 1% CMC+0.5% Tween-80: 30mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。