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Purity: ≥98%
Grazoprevir (formerly MK-5172; MK5172; trade name: Zepatier) is a 2nd generation and selective inhibitor of the Hepatitis C Virus NS3/4A Protease approved by FDA in 2016 for the treatment of hepatitis C (used in combination with elbasvir, an NS5A replication complex inhibitor). It inhibits HCV genotype 1a, 1B, and 4 with IC50 values of 7pM, 4pM, and 62pM, respectively. Grazoprevir has a broad spectrum of anti-HCV activity against various genotypes and resistant variants.
| Targets |
gt1b(Ki=0.01±<0.01 nM);gt1a(Ki=0.01±0.01 nM);gt2a(Ki=0.08±0.02 nM);gt2b(Ki=0.15±0.06 nM);gt3a(Ki=0.90±0.2 nM)
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| ln Vitro |
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.
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| ln Vivo |
Against chimpanzees with chronic HCV infection, MK-5172 (grazoprevir) exhibits a high level of in vivo efficacy. When administered intravenously to dogs, MK-5172 exhibits a low clearance of 5 mL/min/kg and a 3-hour half-life. Following an oral dose of 1 mg/kg, it has a good plasma exposure (AUC=0.4 μM h). Following an oral dose of 1 mg/kg, studies on dog liver biopsy revealed that the liver concentration of MK-5172 was 1.4 μM at the 24-hour mark. Twenty-four hours after oral dosing in dogs, MK-5172 exhibits good liver tissue partitioning and maintains high liver concentration relative to potency, which is consistent with its behavior in rats.
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| Enzyme 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.
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| 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.
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| Animal Protocol |
Rats and Dogs
Research is conducted on rats and dogs. Grazoprevir is formulated in polyethylene glycol 200 (PEG200) and given as a bolus at either 2 mg/kg of body weight (for rats) or 0.5 mg/kg (for dogs) in studies where the drug is dosed intravenously. The compound's crystalline potassium salt is dosed as a solution in PEG400 at 5 mg/kg (for rats) or 1 mg/kg (for dogs) for oral studies.In every study, blood samples are taken at the appropriate times in tubes containing EDTA, and the plasma is separated by centrifugation and kept at -70°C until analysis. After protein precipitation, Grazoprevir (MK-5172) levels are quantified using high-performance liquid chromatography/mass spectroscopy (LC/MS/MS). At the end of the experiment, liver samples are taken from rat studies. After sedation, liver biopsy samples (20 μL) are taken from the dog. Following protein precipitation, tissue samples are homogenized in four volumes of deionized water, and drug concentrations are assessed using LC/MS/MS. |
| References |
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| Molecular Formula |
C38H50N6O9S
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|---|---|
| Molecular Weight |
766.9
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| Exact Mass |
766.34
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| Elemental Analysis |
C, 59.51; H, 6.57; N, 10.96; O, 18.78; S, 4.18
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| CAS # |
1350514-68-9
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| Related CAS # |
Grazoprevir potassium salt;1206524-86-8;Grazoprevir hydrate;1350462-55-3;Grazoprevir sodium salt;1425038-27-2
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| Appearance |
Solid powder
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| SMILES |
O=C([C@H]1N2C([C@H](C(C)(C)C)NC(O[C@]3([H])C[C@@]3([H])CCCCCC4=NC5=CC=C(OC)C=C5N=C4O[C@](C2)([H])C1)=O)=O)N[C@@]6(C(NS(=O)(C7CC7)=O)=O)[C@H](C=C)C6
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| InChi Key |
OBMNJSNZOWALQB-NCQNOWPTSA-N
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| InChi Code |
InChI=1S/C38H50N6O9S/c1-6-22-19-38(22,35(47)43-54(49,50)25-13-14-25)42-32(45)29-18-24-20-44(29)34(46)31(37(2,3)4)41-36(48)53-30-16-21(30)10-8-7-9-11-27-33(52-24)40-28-17-23(51-5)12-15-26(28)39-27/h6,12,15,17,21-22,24-25,29-31H,1,7-11,13-14,16,18-20H2,2-5H3,(H,41,48)(H,42,45)(H,43,47)/t21-,22-,24-,29+,30-,31-,38-/m1/s1
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| Chemical Name |
(33R,35S,91R,92R,5S)-5-(tert-butyl)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalina-3(3,1)-pyrrolidina-9(1,2)-cyclopropanacyclotetradecaphane-35-carboxamide
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| Synonyms |
MK5172; MK 5172; MK-5172; Trade name: Zepatier.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 50~100 mg/mL ( 65.20~130.39 mM )
Ethanol : 66.67~100 mg/mL(86.93 mM ) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.26 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (3.26 mM) Solubility in Formulation 4: 12.5 mg/mL (16.30 mM) in 100% PEG-300 (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3040 mL | 6.5198 mL | 13.0395 mL | |
| 5 mM | 0.2608 mL | 1.3040 mL | 2.6079 mL | |
| 10 mM | 0.1304 mL | 0.6520 mL | 1.3040 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Two-weekin vitropotency of MK-5172 against gt1b replicon cells.Antimicrob Agents Chemother.2012 Aug;56(8):4161-7. |
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MK-5172 demonstrates efficacyin vivoagainst chronic-HCV-infected chimpanzees.Antimicrob Agents Chemother.2012 Aug;56(8):4161-7. |
 Compounds3(A),4(B), and5(C) docked in the gt 1b NS3/4a active site. Cyan = areas of diversity between the gt 1b and gt 3a enzymes. White = conserved areas.ACS Med Chem Lett.2012 Mar 2;3(4):332-6. |
Comparison of the energy-minimized conformations of compounds12(magenta) and14(green) docked in the gt 1b NS3/4a active site.ACS Med Chem Lett.2012 Mar 2;3(4):332-6. |
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 Synthesis of Compound15(MK-5172).ACS Med Chem Lett.2012 Mar 2;3(4):332-6. |
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