Identification

Name
Grazoprevir
Accession Number
DB11575
Description

Grazoprevir is a direct acting antiviral medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients 6. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as Grazoprevir. Grazoprevir is an inhibitor of NS3/4A, a serine protease enzyme, encoded by HCV genotypes 1 and 4 Synthesis. These enzymes are essential for viral replication and serve to cleave the virally encoded polyprotein into mature proteins like NS3, NS4A, NS4B, NS5A and NS5B Label. The barrier for develoment of resistance to NS3/4A inhibitors is lower than that of NS5B inhibitors, another class of DAAs 4. Subtitutions at amino acid positions 155, 156, or 168 are known to confer resistance. The substitutions of the enzyme's catalytic triad consisting of H58, D82, and S139 are also likely to alter the affinity of the drug for NS3/4A or the activity of the enzyme itself. Despite this disadvantage Grazoprevir is still effective against HCV particularly when paired with Elbasvir.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend Grazoprevir as first line therapy in combination with Elbasvir for genotypes 1a, 1b, and 4 of Hepatitis C 4. Grazoprevir and Elbasvir are used with or without Ribavirin with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality 5.

Grazoprevir is available as a fixed dose combination product with Elbasvir (tradename Zepatier) used for the treatment of chronic Hepatitis C. Approved in January 2016 by the FDA, Zepatier is indicated for the treatment of HCV genotypes 1 and 4 with or without Ribavirin depending on the the presence of resistance associated amino acid substitutions in the NS5A protein and previous treatment failure with Ribavirin, Peginterferon alfa-2a, Peginterferon alfa-2b, or other NS3/4A inhibitors like Boceprevir, Simeprevir, or Telaprevir Label. When combined together, Grazoprevir and Elbasvir as the combination product Zepatier have been shown to achieve a SVR between 94% and 97% for genotype 1 and 97% and 100% for genotype 4 after 12 weeks of treatment 6. It can be used in patients with compensated cirrhosis, human immunodeficiency virus co-infection, or severe kidney disease.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 766.903
Monoisotopic: 766.335997918
Chemical Formula
C38H50N6O9S
Synonyms
  • Grazoprevir
  • Grazoprevir anhydrous
External IDs
  • MK 5172
  • MK-5172
  • MK5172

Pharmacology

Indication

Grazoprevir is indicated in combination with Elbasvir (as the fixed dose combination product Zepatier) with or without Ribavirin for treatment of chronic HCV genotypes 1a, 1b, or 4 infection in adults.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Grazoprevir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotypes 1a, 1b, and 4 Label.

Mechanism of action

Grazoprevir is a second generation NS3/4a protease inhibitor used to inhibit viral HCV replication. NS3/4a protease is an integral part of viral replication and mediates the cleavage the virally encoded polyprotein to mature proteins (NS3, NS4A, NS4B, NS5A and NS5B) Label. Grazoprevir inhibits the NS3/4protease enzymes of HCV genotype 1a, 1B, and 4 with IC50 values of 7pM, 4pM, and 62pM, respectively.

TargetActionsOrganism
ANS3/4A protein
antagonist
Hepatitis C Virus
Absorption

Grazoprevir reaches peak plasma concentration 0.5-3 hours after administration Label. Grazoprevir has an absolute bioavailability of 27%. When taken with food the peak concentration of Grazoprevir increases 2.8 fold but this increase in exposure has not been deemed clinically relevant.

Volume of distribution

Grazoprevir has an estimated apparent volume of distribution of 1250 liters Label. It is thought to distribute primarily to the liver with its uptake facilitated by organic anion transporting polypeptide 1B1/3.

Protein binding

Grazoprevir is more than 98.8% bound to plasma proteins Label. It binds both human serum albumin and α1-acid glycoprotein.

Metabolism

Grazoprevir is partially eliminated by oxidative metabolism meditated by CYP3A Label. No circulating metabolites of have been detected in human plasma.

Route of elimination

Grazoprevir is mainly eliminated in the feces (90%) with very little eliminated in the urine (<1%) Label.

Half-life

The geometric mean apparent terminal half-life for Grazoprevir is 31 hours in HCV-infected subjects Label.

Clearance

The clearance of Grazoprevir has not been determined Label.

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

The most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache, and nausea Label.

Affected organisms
  • Hepatitis C Virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Grazoprevir can be increased when it is combined with Abametapir.
AcetylcysteineThe excretion of Grazoprevir can be decreased when combined with Acetylcysteine.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Grazoprevir.
AfatinibThe serum concentration of Grazoprevir can be increased when it is combined with Afatinib.
AmbrisentanThe serum concentration of Grazoprevir can be increased when it is combined with Ambrisentan.
Aminohippuric acidThe excretion of Grazoprevir can be decreased when combined with Aminohippuric acid.
AmiodaroneThe serum concentration of Amiodarone can be increased when it is combined with Grazoprevir.
AmprenavirThe excretion of Grazoprevir can be decreased when combined with Amprenavir.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Grazoprevir.
ApalutamideThe serum concentration of Grazoprevir can be decreased when it is combined with Apalutamide.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take with or without food.

Products

Product Ingredients
IngredientUNIICASInChI Key
Grazoprevir monohydrate4O2AB118LA1350462-55-3RXSARIJMSJWJLZ-CIAYNJNFSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ZepatierGrazoprevir (100 mg) + Elbasvir (50 mg)Tablet, film coatedOralMerck Sharp & Dohme B.V.2016-07-22Not applicableEU flag
ZepatierGrazoprevir (100 mg) + Elbasvir (50 mg)TabletOralMerck Ltd.2016-01-25Not applicableCanada flag
ZepatierGrazoprevir (100 mg/1) + Elbasvir (50 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Corp.2016-01-28Not applicableUS flag

Categories

ATC Codes
J05AP11 — GrazoprevirJ05AP54 — Elbasvir and grazoprevir
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as cyclic peptides. These are compounds containing a cyclic moiety bearing a peptide backbone.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Cyclic peptides
Alternative Parents
Macrolactams / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Quinoxalines / Pyrrolidinecarboxamides / Anisoles / Alkyl aryl ethers / Cyclopropanecarboxylic acids and derivatives / Pyrazines / Heteroaromatic compounds
show 14 more
Substituents
Alkyl aryl ether / Alpha-amino acid amide / Alpha-amino acid or derivatives / Aminosulfonyl compound / Anisole / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbamic acid ester / Carbonic acid derivative
show 30 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
8YE81R1X1J
CAS number
1350514-68-9
InChI Key
OBMNJSNZOWALQB-NCQNOWPTSA-N
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
IUPAC Name
(1R,18R,20R,24S,27S)-24-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl]-7-methoxy-22,25-dioxo-2,21-dioxa-4,11,23,26-tetraazapentacyclo[24.2.1.0^{3,12}.0^{5,10}.0^{18,20}]nonacosa-3(12),4,6,8,10-pentaene-27-carboxamide
SMILES
COC1=CC2=NC3=C(CCCCC[[email protected]@H]4C[[email protected]]4OC(=O)N[[email protected]](C(=O)N4C[[email protected]@H](C[[email protected]]4C(=O)N[[email protected]@]4(C[[email protected]]4C=C)C(=O)NS(=O)(=O)C4CC4)O3)C(C)(C)C)N=C2C=C1

References

Synthesis Reference

Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ: Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor. ACS Med Chem Lett. 2012 Mar 2;3(4):332-6. doi: 10.1021/ml300017p. eCollection 2012 Apr 12.

General References
  1. Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G: MK-5172 : a second-generation protease inhibitor for the treatment of hepatitis C virus infection. Expert Opin Investig Drugs. 2014 May;23(5):719-28. doi: 10.1517/13543784.2014.902049. Epub 2014 Mar 26. [PubMed:24666106]
  2. Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, Koch U, Petrocchi A, Holloway MK, Butcher JW, Romano JJ, Bush KJ, Gilbert KF, McIntyre CJ, Nguyen KT, Nizi E, Carroll SS, Ludmerer SW, Burlein C, DiMuzio JM, Graham DJ, McHale CM, Stahlhut MW, Olsen DB, Monteagudo E, Cianetti S, Giuliano C, Pucci V, Trainor N, Fandozzi CM, Rowley M, Coleman PJ, Vacca JP, Summa V, Liverton NJ: Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor. ACS Med Chem Lett. 2012 Mar 2;3(4):332-6. doi: 10.1021/ml300017p. eCollection 2012 Apr 12. [PubMed:24900473]
  3. Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, Coleman PJ, Dimuzio JM, Ferrara M, Di Filippo M, Gates AT, Graham DJ, Harper S, Hazuda DJ, Huang Q, McHale C, Monteagudo E, Pucci V, Rowley M, Rudd MT, Soriano A, Stahlhut MW, Vacca JP, Olsen DB, Liverton NJ, Carroll SS: MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother. 2012 Aug;56(8):4161-7. doi: 10.1128/AAC.00324-12. Epub 2012 May 21. [PubMed:22615282]
  4. Bagaglio S, Uberti-Foppa C, Morsica G: Resistance Mechanisms in Hepatitis C Virus: implications for Direct-Acting Antiviral Use. Drugs. 2017 May 12. doi: 10.1007/s40265-017-0753-x. [PubMed:28497432]
  5. Myers RP, Shah H, Burak KW, Cooper C, Feld JJ: An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol. 2015 Jan-Feb;29(1):19-34. Epub 2015 Jan 13. [PubMed:25585348]
  6. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
KEGG Drug
D10639
PubChem Compound
44603531
PubChem Substance
347827989
ChemSpider
28506694
RxNav
1734630
ChEBI
132975
ChEMBL
CHEMBL2063090
ZINC
ZINC000095551509
PharmGKB
PA166163437
PDBe Ligand
SUE
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Grazoprevir
PDB Entries
3sud / 3sue / 3suf / 3sug / 6c2m / 6p6q
FDA label
Download (441 KB)
MSDS
Download (175 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
4CompletedPreventionRenal Failure1
4CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
4CompletedTreatmentChronic Kidney Disease stage3 / Hepatitis C Viral Infection1
4CompletedTreatmentEnd Stage Renal Disease (ESRD) / Hepatitis C Viral Infection1
4CompletedTreatmentHemodialysis Treatment / Hepatitis C Viral Infection / Hospital Acquired Infections1
4CompletedTreatmentHepatitis C Viral Infection1
4CompletedTreatmentHepatitis C Viral Infection / Substance Abuse, Intravenous / Substance Use Disorders (SUD)1
4RecruitingBasic ScienceCardiovascular Heart Disease / Hepatitis C Viral Infection / Human Immunodeficiency Virus (HIV) Infections1
4RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Tablet, film coatedOral50 MG
Tablet, coatedOral50 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8871759No2014-10-282031-05-04US flag
US7973040No2011-07-052029-07-24US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0108 mg/mLALOGPS
logP3.26ALOGPS
logP3.35ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)3.77ChemAxon
pKa (Strongest Basic)1.79ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area195.22 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity193.61 m3·mol-1ChemAxon
Polarizability79.37 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Hepatitis C Virus
Pharmacological action
Yes
Actions
Antagonist
General Function
Serine-type peptidase activity
Specific Function
Not Available
Gene Name
NS3/4A
Uniprot ID
B0B3C9
Uniprot Name
Genome polyprotein
Molecular Weight
72789.28 Da

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Zepatier FDA label [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da

Drug created on April 07, 2016 10:40 / Updated on June 12, 2020 10:53

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