1. Metabolic Enzyme/Protease
    Anti-infection
  2. HCV Protease
    HCV

MK-5172 (Synonyms: Grazoprevir; MK 5172; MK5172)

Cat. No.: HY-15298 Purity: 99.58%
Handling Instructions

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.

For research use only. We do not sell to patients.
MK-5172 Chemical Structure

MK-5172 Chemical Structure

CAS No. : 1350514-68-9

Size Price Stock Quantity
Free sample   Apply now  
10 mM * 1 mL in DMSO $118 In-stock
5 mg $90 In-stock
10 mg $140 In-stock
50 mg $450 In-stock
100 mg $650 In-stock
200 mg   Get quote  
500 mg   Get quote  

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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.

IC50 & Target

Ki: 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)[1]

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].

Clinical Trial
Sponsor Condition Start Date Phase
Merck & Co Inc Hepatitis C virus infection 2013-10-31 Phase 2
Merck & Co Inc Hepatitis C virus infection 2013-01-31 Phase 2
Merck & Co Inc Hepatitis C virus infection 2013-02-28 Phase 2
Merck & Co Inc Hepatitis C virus infection 2012-12-31 Phase 2
References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 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
Kinase Assay
[1]

Recombinant HCV NS3/4A enzymes are expressed and purified from Escherichia colias. 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, 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[1].

Animal Administration
[1]

MK-5172 is formulated in polyethylene glycol 200 (PEG200)[1].

Rat and Dog[1]
Studies are performed in both rats and dogs. For studies in which MK-5172 is dosed intravenously to rats or dogs, the compound is formulated in polyethylene glycol 200 (PEG200) and administered as a bolus at either 2 mg/kg of body weight (rat) 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 (rat) or 1 mg/kg (dog). For all studies, blood samples are collected in EDTA-containing tubes at appropriate times and plasma is separated by centrifugation and stored at −70°C until analysis. Quantitation of MK-5172 levels is conducted by high-performance liquid chromatography/mass spectroscopy (LC/MS/MS) following protein precipitation. Liver samples are obtained from rat studies at the termination of the experiment. For dog, liver biopsy samples (20 μL) are collected following sedation. Tissue samples are homogenized in four volumes of deionized water, and drug concentrations are determined by LC/MS/MS after protein precipitation.

References
M.Wt

766.9

Formula

C₃₈H₅₀N₆O₉S

CAS No.

1350514-68-9

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

Purity: 99.58%

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Product Name:
MK-5172
Cat. No.:
HY-15298
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