MK-5172
MK-5172 (CAS No. 1350514-68-9) is a selective inhibitor of hepatitis C virus (HCV) NS3/4A protease [1]. HCV belongs to the genus Hepacivirus in the family Flaviviridae, and its genome is a 9.6-kb positive-strand RNA [2]. Biochemical assays show that MK-5172 inhibits multiple major genotypes and common mutants in HCV NS3/4A protease enzymatic assays; in cell-based replicon systems, the EC?? values for HCV genotypes 1a, 1b, 2a, and 3 are 2 nM, 0.5 nM, 8 nM, and 13 nM, respectively, and it exhibits significant inhibitory activity against genotypes 1a, 2a, 1b, 2b, and 3a [2]. In animal studies, three chronically HCV-infected chimpanzees were dosed at 1 mg/kg twice daily for 7 days: in two chimpanzees infected with high viral titers (~10? IU/ml) of wild-type gt1a or gt1b, viral titers dropped within 2 days to 100 IU/ml and 20 IU/ml, respectively; in another chimpanzee infected with a medium viral titer (~10? IU/ml) of the gt1a NS3 R155K mutant strain, the viral titer rapidly decreased by about 2 log?? units [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.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 766.9 |
| Cas No. | 1350514-68-9 |
| Formula | C38H50N6O9S |
| Synonyms | MK 5172;MK5172,Grazoprevir, |
| Solubility | ≥38.35 mg/mL in DMSO; insoluble in H2O; ≥24 mg/mL in EtOH with gentle warming and ultrasonic |
| SDF | Download SDF |
| Canonical SMILES | COC1=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(NS(C7CC7)(=O)=O)=O)=O)C5)=N2)C=C1 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| 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. |
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Quality Control & MSDS
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Chemical structure
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