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MK-8245

现货
Catalog No.
A4345
有效的肝选择性SCD抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 2,000.00
现货
5mg
¥ 1,890.00
现货
10mg
¥ 2,590.00
现货
50mg
¥ 7,490.00
现货
200mg
¥ 17,290.00
现货

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Background

MK-8245 is a potent and liver-selective inhibitor of stearoyl-CoA desaturase (SCD) with IC50 value of 1nM [1].

SCD1 represents a therapeutic target for the treatment of type II diabetes, dyslipidemia, obesity, and metabolic diseases. As an inhibitor of SCD1, MK-8245 shows potency in both the rat enzyme and hepatocyte assay. There are no significant differences in potencies between the rat, mouse, and human SCD1. MK-8245 is developed as a liver-targeting SCD inhibitor. It demonstrates a liver-targeted tissue distribution profile resulting from a substrate recognition by organic anionic transporter proteins (OATPs) [1, 2].

MK-8245 is effective at lowering glucose level. It can improve glucose clearance dose-dependently with ED50 value of 7mg/kg. In the chronic eDIO mouse study, MK-8245 shows prevention of body weight gain with the maximally efficacious dose of 20 mg/kg bid based on body weight and liver triglyceride reduction [1].

Reference:
[1] Oballa RM, Belair L, Black WC, Bleasby K, Chan CC, Desroches C, Du X, Gordon R, Guay J, Guiral S, Hafey MJ, Hamelin E, Huang Z, Kennedy B, Lachance N, Landry F, Li CS, Mancini J, Normandin D, Pocai A, Powell DA, Ramtohul YK, Skorey K, Srensen D, Sturkenboom W, Styhler A, Waddleton DM, Wang H, Wong S, Xu L, Zhang L.  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.
[2] Lachance N, Guiral S, Huang Z, Leclerc JP, Li CS, Oballa RM, Ramtohul YK, Wang H, Wu J, Zhang L.  Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series. Bioorg Med Chem Lett. 2012 Jan 1;22(1):623-7.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt467.25
Cas No.1030612-90-8
FormulaC17H16BrFN6O4
Solubility≥23.35 mg/mL in DMSO, <2.09 mg/mL in EtOH, <2.11 mg/mL in H2O
Chemical Name2-[5-[3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2-oxazol-5-yl]tetrazol-2-yl]acetic acid
SDFDownload SDF
Canonical SMILESC1CN(CCC1OC2=C(C=CC(=C2)F)Br)C3=NOC(=C3)C4=NN(N=N4)CC(=O)O
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

SCD1酶活性实验

使用大鼠肝脏微粒体或人类SCDl (hSCD-1),通过测定放射性同位素标记的硬脂酰辅酶A转化为油酰辅酶A,以评价MK-8245对硬脂酰辅酶A去饱和酶的作用。雄性Wistar或Spraque Dawley大鼠进行高碳水化合物饮食。3天后,收获肝脏微粒体。使用含250 mM蔗糖,1 mM EDTA,5 mM DTT和50 mM Tris-HCl (pH 7.5) 的缓冲液,将肝脏按 (1:10 w/v) 分布均匀。按100,000 × g转速离心60分钟,将肝脏微粒体悬浮于含100 mM磷酸钠,20%甘油,2 mM DTT的缓冲液中,将其储存于-78 °C。使用人类SCDl(产生于杆状病毒Sf9表达系统)、细胞色素B5和细胞色素B5还原酶重新构建人类SCDl去饱和酶系统。将不同浓度的MK-8245溶于2 μL DMSO中,再加入180 μL SCD酶?(缓冲液组成:100 mM Tris-HCl (pH 7.5),ATP (5 mM),辅酶A (0.1 mM),Triton X-100 (0.5 mM) 和NADH (2 mM)),将其置于在室温下,温育15分钟。加入20 μL [3H]硬脂酰辅酶A(终浓度为2 μM,,放射性浓度为1 μCi/mL),开始反应。10分钟后,80 μL反应混合物与CaCl2/木炭水悬浮液((10% w) 和25 μL CaCl2 (2N))混合。离心后,沉淀具有放射活性的脂肪酸,使用闪烁计数器测定9,10-[3H]-硬脂酰辅酶A释放的氚化水(由SCD酶介导)。

细胞实验 [1]:

细胞系

大鼠肝细胞

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

< 200 nM

实验结果

在大鼠肝细胞(含具有功能的活性OATPs)中,MK-8245显著抑制SCD,其IC50值为68 nM。

动物实验 [1]:

动物模型

eDIO小鼠

给药剂量

3、10或30 mg/kg;口服给药

实验结果

MK-8245是一种肝靶向的小分子SCD抑制剂,能改善全身胰岛素敏感性。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Oballa RM, Belair L, Black WC, Bleasby K, Chan CC, Desroches C, Du X, Gordon R, Guay J, Guiral S, Hafey MJ, Hamelin E, Huang Z, Kennedy B, Lachance N, Landry F, Li CS, Mancini J, Normandin D, Pocai A, Powell DA, Ramtohul YK, Skorey K, S?rensen D, Sturkenboom W, Styhler A, Waddleton DM, Wang H, Wong S, Xu L, Zhang L. 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.

生物活性

描述 MK-8245是一种有效的肝硬脂酰辅酶A脱氢酶(SCD)选择性抑制剂。
靶点 SCD1 (human) SCD1 (rat) SCD1 (mouse)      
IC50 1 nM 3 nM 3 nM      

质量控制

化学结构

MK-8245