MK-5172
(Synonyms: 格拉瑞韦; MK-5172) 目录号 : GC18004
An NS3/4A protease inhibitor
Cas No.:1350514-68-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Kinase experiment [1]: | |
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Inhibitory assays |
Inhibition of HCV NS3/4A protease activity in reaction mixtures containing MK-5172, vaniprevir, or the reference compounds danoprevir and TMC435 was determined in a time-resolved fluorescence assay. Cell-based HCV replicon assays were conducted in genotype 1b (con1) stable cell line HB1 (26) or a gt2a cell line (JFH) in the presence of either 10% fetal bovine serum (FBS) or 40% normal human serum (NHS). For in vitro resistance selections, 100,000 HB1 cells were seeded into a T162 Z-top flask and cultured in the presence of 0.5 mg/ml G418 and the desired concentration of MK-5172. Cells were cultured for approximately 3 weeks with regular exchanges of medium until sufficient cell death had occurred to enable distinct colonies to form. After expansion, total RNA was isolated, used as a template to generate NS3/4a cDNA, and sequenced using conventional molecular biology techniques. |
| Cell experiment [1]: | |
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Cell lines |
A genotype/mutant panel of stable replicon cell lines |
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Preparation method |
The solubility of this compound in DMSO is >38.4mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
2-10 nM, 3 weeks |
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Applications |
MK-5172 demonstrated subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a. MK-5172 was efficacious across the genetically diverse range of genotype 1 infections encountered in clinical settings with EC50s ranged narrowly between 0.3 and 5.9 nM. In Genotype 1b replicon cells, pre- treatment with MK-5172 resulted in little apparent cell growth and limited recovery of replicon RNA levels. |
| Animal experiment [1]: | |
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Animal models |
Chimpanzees, Dogs, Rats |
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Dosage form |
Oral administration, 1 mg/kg, twice daily for 7 days |
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Application |
MK-5172 demonstrated low to moderate clearance and a modest half-life in both rat and dog. Oral administration of MK-5172 (1 mg/kg) demonstrated modest bioavailability of 12 to 13%, with moderate plasma exposure in both species. The 24-h trough liver concentrations were 0.2 μM in rat and 1.4 μM in dog (1 mg/kg), yielding exposure multiples of 27- to 200-fold over the serum-adjusted replicon EC50. In chronic-HCV-infected chimpanzees harboring gt1a, gt1b, or gt1a NS3 R155K infections, treatment with MK-5172 (1 mg/kg, b.i.d.) demonstrated efficacy in vivo. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Summa, V., Ludmerer, S. W., McCauley, J. A., Fandozzi, C., Burlein, C., Claudio, G., ... & Gates, A. T. (2012). MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrobial agents and chemotherapy, AAC-00324. | |
MK-5172 is a selective inhibitor of Hepatitis C Virus NS3/4a Protease [1].
Hepatitis C (HCV) virus is a member of the Flaviviridae family of viruses in the Hepacivirus genus and encoded by a 9.6-kb positive strand RNA genome [2].
In biochemical assays, MK-5172 inhibited a series of major genotypes and common mutants in a HCV NS3/4A protease enzymatic assay. In a cell-based replicon system, MK-5172 inhibited HCV with EC50 values of 2 nM against genotype 1a, 0.5 nM against genotype 1b, 8 nM against genotype 2a and 13 nM against genotype 3. Also, MK-5172 is effective against HCV genotypes 1a, 2a, 1b, 2b and 3a [2].
Treatment three chronically HCV-infected chimpanzees with a dose of 1 mg/kg twice daily for 7 days, Two of the chimpanzees had wild-type (WT) gt1a or gt1b infections with high viral titers (~106 IU/ml). A third chimpanzee had a modest viral titer (~104 IU/ml) that was gt1a NS3 R155K virus. MK-5172 (1 mg/kg) reduced viral titer of the gt1a (WT) infection to ~100 IU/ml within 2 days and the gt1b infection to 20 IU/ml. The gt1a NS3 R155K-infected chimp experienced a rapid ~2-log reduction in viral titer [2].
References:
[1]. Harper S, McCauley JA, Rudd MT, et al. Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor. ACS Med Chem Lett, 2012, 3(4): 332-336.
[2]. Summa V, Ludmerer SW, McCauley JA, et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother, 2012, 56(8): 4161-4167.
| Cas No. | 1350514-68-9 | SDF | |
| 别名 | 格拉瑞韦; MK-5172 | ||
| Canonical SMILES | COC1=CC2=C(N=C(CCCCC[C@@H]3C[C@H]3OC(N[C@@H](C(C)(C)C)C(N4[C@H](C(N[C@@]5(C(NS(=O)(C6CC6)=O)=O)[C@H](C5)C=C)=O)C[C@@H]7C4)=O)=O)C(O7)=N2)C=C1 | ||
| 分子式 | C38H50N6O9S | 分子量 | 766.9 |
| 溶解度 | ≥ 38.35 mg/mL in DMSO, ≥ 24 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 | 1.304 mL | 6.5198 mL | 13.0395 mL |
| 5 mM | 0.2608 mL | 1.304 mL | 2.6079 mL |
| 10 mM | 0.1304 mL | 0.652 mL | 1.304 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。