MK-5172HCV NS3/4a protease inhibitor CAS# 1350514-68-9 |
- MK-5172 potassium salt
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- MK-5172 hydrate
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- MK-5172 sodium salt
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Quality Control & MSDS
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| Cas No. | 1350514-68-9 | SDF | Download SDF |
| PubChem ID | 44603531 | Appearance | Powder |
| Formula | C38H50N6O9S | M.Wt | 766.9 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | Grazoprevir | ||
| Solubility | DMSO : 50 mg/mL (65.20 mM; Need ultrasonic) H2O : < 0.1 mg/mL (insoluble) | ||
| SMILES | CC(C)(C)C1C(=O)N2CC(CC2C(=O)NC3(CC3C=C)C(=O)NS(=O)(=O)C4CC4)OC5=NC6=C(C=CC(=C6)OC)N=C5CCCCCC7CC7OC(=O)N1 | ||
| Standard InChIKey | OBMNJSNZOWALQB-NCQNOWPTSA-N | ||
| Standard InChI | 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 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | MK-5172 is a selective inhibitor of Hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants, with Ki of 0.01 nM (gt1b), 0.01 nM (gt1a), 0.08 nM (gt2a), 0.15 nM (gt2b), 0.90 nM (gt3a), respectively.In Vitro:In biochemical assays, MK-5172 is effective against a panel of 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)[1]. 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[2].In Vivo:MK-5172 demonstrates efficacy in vivo against chronic-HCV-infected chimpanzees[1]. 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[2]. References: | |||||
MK-5172 Dilution Calculator
MK-5172 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.304 mL | 6.5198 mL | 13.0395 mL | 26.079 mL | 32.5988 mL |
| 5 mM | 0.2608 mL | 1.304 mL | 2.6079 mL | 5.2158 mL | 6.5198 mL |
| 10 mM | 0.1304 mL | 0.652 mL | 1.304 mL | 2.6079 mL | 3.2599 mL |
| 50 mM | 0.0261 mL | 0.1304 mL | 0.2608 mL | 0.5216 mL | 0.652 mL |
| 100 mM | 0.013 mL | 0.0652 mL | 0.1304 mL | 0.2608 mL | 0.326 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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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.
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The Discovery of Quinoxaline-Based Metathesis Catalysts from Synthesis of Grazoprevir (MK-5172).[Pubmed:27123552]
Org Lett. 2016 May 6;18(9):1952-5.
Olefin metathesis (OM) is a reliable and practical synthetic methodology for challenging carbon-carbon bond formations. While existing catalysts can effect many of these transformations, the synthesis and development of new catalysts is essential to increase the application breadth of OM and to achieve improved catalyst activity. The unexpected initial discovery of a novel olefin metathesis catalyst derived from synthetic efforts toward the HCV therapeutic agent grazoprevir (MK-5172) is described. This initial finding has evolved into a class of tunable, shelf-stable ruthenium OM catalysts that are easily prepared and exhibit unique catalytic activity.
Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172.[Pubmed:26682473]
ACS Chem Biol. 2016 Apr 15;11(4):900-9.
Recent advances in direct-acting antivirals against Hepatitis C Virus (HCV) have led to the development of potent inhibitors, including MK-5172, that target the viral NS3/4A protease with relatively low susceptibility to resistance. MK-5172 has a P2-P4 macrocycle and a unique binding mode among current protease inhibitors where the P2 quinoxaline packs against the catalytic residues H57 and D81. However, the effect of macrocyclization on this binding mode is not clear, as is the relation between macrocyclization, thermodynamic stabilization, and susceptibility to the resistance mutation A156T. We have determined high-resolution crystal structures of linear and P1-P3 macrocyclic analogs of MK-5172 bound to WT and A156T protease and compared these structures, their molecular dynamics, and experimental binding thermodynamics to the parent compound. We find that the "unique" binding mode of MK-5172 is conserved even when the P2-P4 macrocycle is removed or replaced with a P1-P3 macrocycle. While beneficial to decreasing the entropic penalty associated with binding, the constraint exerted by the P2-P4 macrocycle prevents efficient rearrangement to accommodate the A156T mutation, a deficit alleviated in the linear and P1-P3 analogs. Design of macrocyclic inhibitors against NS3/4A needs to achieve the best balance between exerting optimal conformational constraint for enhancing potency, fitting within the substrate envelope and allowing adaptability to be robust against resistance mutations.
