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Grazoprevir sodium salt
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
Grazoprevir sodium salt图片
CAS NO:1425038-27-2
规格:≥98%
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW) 788.89
Formula C38H49N6O9SNa
CAS No.1425038-27-2 (sodium salt);
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO:>100 mg/mL
Water: N/A
Ethanol: >100 mg/mL
Chemical NameChemical Name: sodium ((1R,2S)-1-((33R,35S,91R,92R,5S)-5-(tert-butyl)-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalina-3(3,1)-pyrrolidina-9(1,2)-cyclopropanacyclotetradecaphane-35-carboxamido)-2-vinylcyclopropane-1-carbonyl)(cyclopropylsulfonyl)amide
SynonymsMK5172 Na; MK 5172 sodium; MK-5172 sodium, Trade name: Zepatier?.
SMILES CodeCOC1=CC2=C(N=C(CCCCC[C@@H]3C[C@H]3OC4=O)C(O[C@H]5CN(C([C@H](C(C)(C)C)N4)=O)[C@H](C(N[C@@]([C@@H]6C=C)(C6)C([N-]S(C7CC7)(=O)=O)=O)=O)C5)=N2)C=C1.[Na+]
实验参考方法
In Vitro

In vitro activity: MK-5172 (Grazoprevir) is effective in biochemical assays against major genotypes and variants engineered with common resistant mutations, with Ki of 0.01±<0.01 nM (gt1b), 0.01±0.01 nM (gt1a), 0.08±0.02 nM (gt2a), 0.15±0.06 nM (gt2b), 0.90±0.2 nM (gt3a), 0.07±0.01 nM (gt1bR155K), 0.14±0.03 nM (gt1bD168V), 0.30±0.04 nM (gt1bD168Y), 5.3±0.9 nM (gt1bA156T), and 12±2 nM (gt1bA156V), respectively. In the replicon assay, MK-5172 demonstrates subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a, with EC50s of 0.5±0.1 nM, 2±1 nM, and 2±1 nM for gt1bcon1, gt1a, and gt2a, respectively. MK-5172 is potent against a panel of HCV replication mutants NS5A (Y93H) (EC50=0.7±0.3 nM), NS5B nucleosides (S282T) (EC50=0.3±0.1 nM), and NS5B (C316Y) (EC50=0.4±0.2). MK-5172 maintains the excellent potency against the gt 3a enzyme as well as a broad panel of mutant enzymes, has excellent potency in the replicon system [gt1b IC50(50% NHS)=7.4 nM; gt1a IC50(40% NHS)=7 nM], and shows excellent rat liver exposure.


Kinase Assay: recombinant HCV NS3/4A enzymes are expressed and purified from E. Coli. Enzyme sequences are derived from genotype 1a (gt1a) H77, gt1b con1, gt2a JFH1, gt2b HCJ8, and gt3a NZL1. Inhibition of HCV NS3/4A protease activity in reaction mixtures containing MK-5172 (Grazoprevir), Vaniprevir, or the reference compounds Danoprevir and TMC435 is determined in a time-resolved fluorescence assay. Cell-based HCV replicon assays are conducted in genotype 1b (con1) stable cell line HB1 or a gt2a cell line (JFH) in the presence of either 10% fetal bovine serum (FBS) or 40% normal human serum (NHS). Determinations of 50% effective concentrations (EC50s) against the panel of genotype or mutant replicon cell lines are conducted using a TaqMan-based assay. The 50% cytotoxic concentration (CC50) is determined in the HCV replicon cell line with the use of an MTS assay. Potency determinations against clinical genotype 1 NS3/4A sequences are made using a transient cell-based phenotype assay. The NS3/4A patient isolates are cloned from human plasma infected with HCV. Broad counterscreening, in which MK-5172 is evaluated for its inhibitory potency at a concentration of 10 μM, is conducted at MDS Pharma Services.


Cell Assay: HB1 cells (30,000 per well) are seeded of a 6-well tissue culture plate per drug concentration. The next day (day 0), the medium is replenished with fresh medium and MK-5172 at the appropriate drug concentration. Cells from a single well per drug concentration are harvested on days 0, 1, and 2, washed, and stored frozen until evaluation. The fourth well is similarly harvested on day 3.5 except that 30,000 cells are reseeded with fresh medium and MK-5172 at the appropriate drug concentration. For additional time points, cells are passaged and harvested every one-half week for 2 weeks. For the third week, cells are similarly treated except that cells received replenishing medium which contained 0.5 mg/ml G418 without protease inhibitor.

In VivoMK-5172 (Grazoprevir) demonstrates high in vivo efficacy against chronic-HCV-infected chimpanzees. When dosed to dogs, MK-5172 shows low clearance of 5 mL/min/kg and a 3 h half-life after iv dosing and has good plasma exposure (AUC=0.4 μM h) after a 1 mg/kg oral dose. Dog liver biopsy studies showed that the liver concentration of MK-5172 after the 1 mg/kg oral dose is 1.4 μM at the 24 h time point. Similar to its behavior in rats, MK-5172 demonstrates effective partitioning into liver tissue and maintains high liver concentration, relative to potency, 24 h after oral dosing in dogs.
Animal model Rat and dog
Formulation & Dosage Formulated in polyethylene glycol 200 (PEG200); administered as a bolus at either 2 mg/kg of body weight (Rats) or 0.5 mg/kg (dog). For oral studies, the crystalline potassium salt of the compound is dosed as a solution in PEG400 at 5 mg/kg (Rats) or 1 mg/kg (dog).
References Antimicrob Agents Chemother. 2012 Aug;56(8):4161-7.