MK 0893
(Synonyms: N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘基)-1H-吡唑-1-基]乙基]苯甲酰]-BETA-丙氨酸,MK0893; MK-0893) 目录号 : GC14793
MK 0893是一种有效，选择性的胰高血糖素受体（GCGR，glucagon receptor）拮抗剂，IC50 值为6.6 nM。
Cas No.:870823-12-4
Sample solution is provided at 25 µL, 10mM.
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MK 0893 is a potent and selective glucagon receptor (GCGR) antagonist with an IC50 value of 6.6 nM[1]. The mechanism of action of MK 0893 is to prevent GCGR activation by limiting the movement of transmembrane helix 6 (TM6) protein required for G protein signaling [2]. MK-0893 treats patients with type 2 diabetes and effectively reduces postprandial blood sugar, but it will cause an increase in liver transaminases and is not suitable for clinical development [3].
In vitro, MK 0893 (0-1000nM) treated human primary liver cells for 1 hour, inhibited the effect of glucagon and prevented it from inducing the production of cAMP, with an IC50 value of 563nM [4]. MK 0893 (0-400nM) treated INS-1 832/13 cells and inhibited the effects of glucagon and also inhibited the effects of glucagon-like peptide-1 (GLP-1) [5].
In vivo, oral administration of MK 0893 (3, 10 mg/kg) to hGCGR ob/ob mice reduced blood glucose levels by 32% and 39% at single doses of 3 and 10 mg/kg, respectively [1]. MK 0893 (3, 10 mg/kg) administered orally to WT and hGCGR mice did not significantly affect plasma cholesterol or plant sterol levels in WT mice, however, at a dose of 10 mg/kg, it significantly increased campesterol levels. In hGCGR mice, MK 0893 exhibited a dose-dependent increase in plasma sitosterol levels [4].
References:
[1] Xiong Y, Guo J, Candelore M R, et al. Discovery of a Novel Glucagon Receptor AntagonistN-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1 H-pyrazol-1-yl] ethyl} phenyl) carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes[J]. Journal of medicinal chemistry, 2012, 55(13): 6137-6148.
[2] Crunkhorn S. Glucagon receptor antagonist binding site identified[J]. Nature Reviews Drug Discovery, 2016, 15(6): 384-384.
[3] Christensen M, Bagger J I, Vilsboll T, et al. The alpha-cell as target for type 2 diabetes therapy[J]. The review of diabetic studies: RDS, 2011, 8(3): 369.
[4] Guan H P, Yang X, Lu K, et al. Glucagon receptor antagonism induces increased cholesterol absorption [S][J]. Journal of lipid research, 2015, 56(11): 2183-2195.
[5] Chepurny O G, Matsoukas M T, Liapakis G, et al. Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP[J]. Journal of Biological Chemistry, 2019, 294(10): 3514-3531.
MK 0893是一种有效，选择性的胰高血糖素受体（GCGR，glucagon receptor）拮抗剂，IC50 值为6.6 nM[1]。 MK 0893的作用机制是通过限制G蛋白信号传导所需的跨膜螺旋6（TM6）蛋白运动来防止GCGR激活[2]。MK-0893治疗2 型糖尿病患者，有效降低餐后血糖，但会造成肝脏转氨酶指标升高而不适用于临床开发[3]。
在体外，MK 0893（0-1000nM）处理人原代肝细胞1 h，抑制了胰高血糖素的作用，阻止其诱导cAMP的产生，IC50 值为563nM[4]。MK 0893（0-400nM）处理INS-1 832/13细胞，抑制了胰高血糖素的作用，还抑制了胰高血糖素样肽-1（GLP-1）的作用[5]。
在体内，MK 0893（3，10mg/kg）通过口服给药治疗hGCGR ob/ob小鼠，在3 和10mg/kg单剂量下分别使血糖水平降低了32%和39%[1]。MK 0893（3，10mg/kg）通过口服给药治疗WT和hGCGR小鼠，对WT小鼠的血浆胆固醇或植物甾醇水平没有显著影响，但在10mg/kg时显著增加了菜油甾醇水平，对hGCGR小鼠的血浆谷甾醇水平呈剂量依赖性增加趋势[4]。
Cell experiment [1]: | |
Cell lines | Human primary hepatocytes |
Preparation method | 4,000 cells per well were preincubated with MK-0893, GRA1, and GRA2 (0-1000nM) for 30 min and restimulated with glucagon (5nM) for 30 min at room temperature. |
Reaction Conditions | 0-1000nM; 1 h |
Applications | In the presence of glucagon, MK-0893, GRA1, and GRA2 all inhibit cAMP production with IC50 of 563, 448, and 292 nM, respectively. |
Animal experiment [2]: | |
Animal models | hGCGR ob/ob mice |
Preparation method | hGCGR ob/ob mice at 1 h post MK 0893 (3, 10mg/kg) administration via po, glucagon dissolved in PBS was injected at 15μg/kg ip followed by glucose measurements using a glucometer via tail bleeding. |
Dosage form | 3, 10mg/kg; p.o. |
Applications | MK 0893 at 10 and 3 mg/kg oral doses lowered blood glucose level by 39%, 32% respectively. |
References: [1] Guan H P, Yang X, Lu K, et al. Glucagon receptor antagonism induces increased cholesterol absorption [S][J]. Journal of lipid research, 2015, 56(11): 2183-2195. [2] Xiong Y, Guo J, Candelore M R, et al. Discovery of a Novel Glucagon ReceptorAntagonistN-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1 H-pyrazol-1-yl] ethyl} phenyl) carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes[J]. Journal of medicinal chemistry, 2012, 55(13): 6137-6148. | |
| Cas No. | 870823-12-4 | SDF | |
| 别名 | N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘基)-1H-吡唑-1-基]乙基]苯甲酰]-BETA-丙氨酸,MK0893; MK-0893 | ||
| 化学名 | 3-[[4-[(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid | ||
| Canonical SMILES | CC(C1=CC=C(C=C1)C(=O)NCCC(=O)O)N2C(=CC(=N2)C3=CC(=CC(=C3)Cl)Cl)C4=CC5=C(C=C4)C=C(C=C5)OC | ||
| 分子式 | C32H27Cl2N3O4 | 分子量 | 588.48 |
| 溶解度 | ≥ 24.05 mg/mL in DMSO, ≥ 4.8 mg/mL in EtOH with ultrasonic and warming | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6993 mL | 8.4965 mL | 16.9929 mL |
| 5 mM | 0.3399 mL | 1.6993 mL | 3.3986 mL |
| 10 mM | 0.1699 mL | 0.8496 mL | 1.6993 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Quality Control & SDS
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- Purity: >99.00%
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