Identification
NameGrazoprevir
Accession NumberDB11575
TypeSmall Molecule
GroupsApproved
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 [FDA 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 [FDA 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.

Structure
Thumb
Synonyms
(1aR,5S,8S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl}-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide
Grazoprevir
Grazoprevir anhydrous
External IDs MK 5172 / MK-5172 / MK-5172 ANHYDROUS / MK5172
Product Ingredients
IngredientUNIICASInChI KeyDetails
Grazoprevir monohydrate4O2AB118LA 1350462-55-3RXSARIJMSJWJLZ-CIAYNJNFSA-NDetails
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
ZepatierTablet, film coatedOralMerck Sharp & Dohme Limited2016-07-22Not applicableEu
Categories
UNII8YE81R1X1J
CAS number1350514-68-9
WeightAverage: 766.903
Monoisotopic: 766.335997918
Chemical FormulaC38H50N6O9S
InChI KeyOBMNJSNZOWALQB-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)-C-hydroxycarbonimidoyl]-2-ethenylcyclopropyl]-22-hydroxy-7-methoxy-25-oxo-2,21-dioxa-4,11,23,26-tetraazapentacyclo[24.2.1.0³,¹².0⁵,¹⁰.0¹⁸,²⁰]nonacosa-3(12),4,6,8,10,22-hexaene-27-carboximidic acid
SMILES
[H][C@@]12C[C@@]1([H])OC(O)=N[C@]([H])(C(=O)N1C[C@@]([H])(C[C@@]1([H])C(O)=N[C@@]1(C[C@@]1([H])C=C)C(O)=NS(=O)(=O)C1CC1)OC1=C(CCCCC2)N=C2C=CC(OC)=CC2=N1)C(C)(C)C
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.

Structured Indications
Pharmacodynamics

Grazoprevir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotypes 1a, 1b, and 4 [FDA 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) [FDA Label]. Grazoprevir inhibits the NS3/4protease enzymes of HCV genotype 1a, 1B, and 4 with IC50 values of 7pM, 4pM, and 62pM, respectively.

TargetKindPharmacological actionActionsOrganismUniProt ID
NS3/4A proteinProteinyes
antagonist
Hepatitis C virusB0B3C9 details
Related Articles
Absorption

Grazoprevir reaches peak plasma concentration 0.5-3 hours after administration [FDA 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 [FDA 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 [FDA Label]. It binds both human serum albumin and α1-acid glycoprotein.

Metabolism

Grazoprevir is partially eliminated by oxidative metabolism meditated by CYP3A [FDA 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%) [FDA Label].

Half life

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

Clearance

The clearance of Grazoprevir has not been determined [FDA Label].

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 [FDA Label].

Affected organisms
  • Hepatitis C Virus
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetaminophenThe serum concentration of Grazoprevir can be increased when it is combined with Acetaminophen.Approved
AfatinibThe serum concentration of Grazoprevir can be increased when it is combined with Afatinib.Approved
AlbendazoleThe serum concentration of Grazoprevir can be increased when it is combined with Albendazole.Approved, Vet Approved
AldosteroneThe serum concentration of Grazoprevir can be decreased when it is combined with Aldosterone.Experimental
AlectinibThe serum concentration of Grazoprevir can be increased when it is combined with Alectinib.Approved
AlfentanilThe serum concentration of Grazoprevir can be increased when it is combined with Alfentanil.Approved, Illicit
AmantadineThe serum concentration of Grazoprevir can be increased when it is combined with Amantadine.Approved
Aminohippuric acidThe serum concentration of Grazoprevir can be increased when it is combined with Aminohippuric acid.Approved
AmiodaroneThe serum concentration of Grazoprevir can be decreased when it is combined with Amiodarone.Approved, Investigational
AmitriptylineThe serum concentration of Grazoprevir can be increased when it is combined with Amitriptyline.Approved
AmlodipineThe serum concentration of Grazoprevir can be increased when it is combined with Amlodipine.Approved
AmprenavirThe serum concentration of Grazoprevir can be decreased when it is combined with Amprenavir.Approved
AmsacrineThe serum concentration of Grazoprevir can be increased when it is combined with Amsacrine.Approved
AstemizoleThe serum concentration of Grazoprevir can be increased when it is combined with Astemizole.Approved, Withdrawn
AtazanavirThe serum concentration of Grazoprevir can be increased when it is combined with Atazanavir.Approved, Investigational
AtenololThe serum concentration of Grazoprevir can be increased when it is combined with Atenolol.Approved
AtorvastatinThe serum concentration of Grazoprevir can be increased when it is combined with Atorvastatin.Approved
AzelastineThe serum concentration of Grazoprevir can be increased when it is combined with Azelastine.Approved
AzithromycinThe serum concentration of Grazoprevir can be increased when it is combined with Azithromycin.Approved
BenzocaineThe serum concentration of Grazoprevir can be increased when it is combined with Benzocaine.Approved
BepridilThe serum concentration of Grazoprevir can be increased when it is combined with Bepridil.Approved, Withdrawn
BiperidenThe serum concentration of Grazoprevir can be increased when it is combined with Biperiden.Approved
BosutinibThe serum concentration of Grazoprevir can be increased when it is combined with Bosutinib.Approved
BromocriptineThe serum concentration of Grazoprevir can be increased when it is combined with Bromocriptine.Approved, Investigational
BuprenorphineThe serum concentration of Grazoprevir can be increased when it is combined with Buprenorphine.Approved, Illicit, Investigational, Vet Approved
BuspironeThe serum concentration of Grazoprevir can be increased when it is combined with Buspirone.Approved, Investigational
CabazitaxelThe serum concentration of Grazoprevir can be increased when it is combined with Cabazitaxel.Approved
CaffeineThe serum concentration of Grazoprevir can be increased when it is combined with Caffeine.Approved
CanagliflozinThe serum concentration of Grazoprevir can be increased when it is combined with Canagliflozin.Approved
CandesartanThe serum concentration of Grazoprevir can be increased when it is combined with Candesartan.Approved
CaptoprilThe serum concentration of Grazoprevir can be increased when it is combined with Captopril.Approved
CarbamazepineThe serum concentration of Grazoprevir can be decreased when it is combined with Carbamazepine.Approved, Investigational
CarvedilolThe serum concentration of Grazoprevir can be increased when it is combined with Carvedilol.Approved, Investigational
CaspofunginThe serum concentration of Grazoprevir can be increased when it is combined with Caspofungin.Approved
ChloroquineThe serum concentration of Grazoprevir can be increased when it is combined with Chloroquine.Approved, Vet Approved
ChlorpromazineThe serum concentration of Grazoprevir can be increased when it is combined with Chlorpromazine.Approved, Vet Approved
ChlorpropamideThe serum concentration of Grazoprevir can be increased when it is combined with Chlorpropamide.Approved
ChlorprothixeneThe serum concentration of Grazoprevir can be increased when it is combined with Chlorprothixene.Approved, Withdrawn
CholesterolThe serum concentration of Grazoprevir can be increased when it is combined with Cholesterol.Experimental
Cholic AcidThe serum concentration of Grazoprevir can be decreased when it is combined with Cholic Acid.Approved
CilazaprilThe serum concentration of Grazoprevir can be increased when it is combined with Cilazapril.Approved
CimetidineThe serum concentration of Grazoprevir can be decreased when it is combined with Cimetidine.Approved
CiprofloxacinThe serum concentration of Grazoprevir can be increased when it is combined with Ciprofloxacin.Approved, Investigational
CitalopramThe serum concentration of Grazoprevir can be increased when it is combined with Citalopram.Approved
ClarithromycinThe serum concentration of Grazoprevir can be increased when it is combined with Clarithromycin.Approved
ClofazimineThe serum concentration of Grazoprevir can be increased when it is combined with Clofazimine.Approved, Investigational
ClomipramineThe serum concentration of Grazoprevir can be increased when it is combined with Clomipramine.Approved, Vet Approved
ClotrimazoleThe serum concentration of Grazoprevir can be decreased when it is combined with Clotrimazole.Approved, Vet Approved
CobicistatThe serum concentration of Grazoprevir can be increased when it is combined with Cobicistat.Approved
ColchicineThe serum concentration of Grazoprevir can be increased when it is combined with Colchicine.Approved
ColforsinThe serum concentration of Grazoprevir can be increased when it is combined with Colforsin.Experimental
CrizotinibThe serum concentration of Grazoprevir can be increased when it is combined with Crizotinib.Approved
CyclophosphamideThe serum concentration of Grazoprevir can be increased when it is combined with Cyclophosphamide.Approved, Investigational
CyclosporineThe serum concentration of Grazoprevir can be decreased when it is combined with Cyclosporine.Approved, Investigational, Vet Approved
DaclatasvirThe serum concentration of Grazoprevir can be increased when it is combined with Daclatasvir.Approved
DactinomycinThe serum concentration of Grazoprevir can be increased when it is combined with Dactinomycin.Approved
DasatinibThe serum concentration of Grazoprevir can be increased when it is combined with Dasatinib.Approved, Investigational
DaunorubicinThe serum concentration of Grazoprevir can be decreased when it is combined with Daunorubicin.Approved
DesipramineThe serum concentration of Grazoprevir can be increased when it is combined with Desipramine.Approved
DesloratadineThe serum concentration of Grazoprevir can be increased when it is combined with Desloratadine.Approved, Investigational
DexamethasoneThe serum concentration of Grazoprevir can be decreased when it is combined with Dexamethasone.Approved, Investigational, Vet Approved
DextromethorphanThe serum concentration of Grazoprevir can be increased when it is combined with Dextromethorphan.Approved
DiclofenacThe serum concentration of Grazoprevir can be increased when it is combined with Diclofenac.Approved, Vet Approved
DigoxinThe serum concentration of Grazoprevir can be decreased when it is combined with Digoxin.Approved
DihydroergotamineThe serum concentration of Grazoprevir can be increased when it is combined with Dihydroergotamine.Approved
DiltiazemThe serum concentration of Grazoprevir can be increased when it is combined with Diltiazem.Approved
DipyridamoleThe serum concentration of Grazoprevir can be increased when it is combined with Dipyridamole.Approved
DoxazosinThe serum concentration of Grazoprevir can be increased when it is combined with Doxazosin.Approved
DoxepinThe serum concentration of Grazoprevir can be increased when it is combined with Doxepin.Approved
DoxorubicinThe serum concentration of Grazoprevir can be decreased when it is combined with Doxorubicin.Approved, Investigational
DronabinolThe serum concentration of Grazoprevir can be increased when it is combined with Dronabinol.Approved, Illicit
DronedaroneThe serum concentration of Grazoprevir can be increased when it is combined with Dronedarone.Approved
ElbasvirThe serum concentration of Grazoprevir can be increased when it is combined with Elbasvir.Approved
EltrombopagThe serum concentration of Grazoprevir can be increased when it is combined with Eltrombopag.Approved
EnalaprilThe serum concentration of Grazoprevir can be increased when it is combined with Enalapril.Approved, Vet Approved
EnzalutamideThe serum concentration of Grazoprevir can be increased when it is combined with Enzalutamide.Approved
ErgonovineThe serum concentration of Grazoprevir can be increased when it is combined with Ergonovine.Approved
ErgotamineThe serum concentration of Grazoprevir can be increased when it is combined with Ergotamine.Approved
ErythromycinThe serum concentration of Grazoprevir can be decreased when it is combined with Erythromycin.Approved, Vet Approved
EstramustineThe serum concentration of Grazoprevir can be increased when it is combined with Estramustine.Approved
EstriolThe serum concentration of Grazoprevir can be decreased when it is combined with Estriol.Approved, Vet Approved
EstroneThe serum concentration of Grazoprevir can be decreased when it is combined with Estrone.Approved
EtoposideThe serum concentration of Grazoprevir can be increased when it is combined with Etoposide.Approved
EtravirineThe serum concentration of Grazoprevir can be increased when it is combined with Etravirine.Approved
FelodipineThe serum concentration of Grazoprevir can be increased when it is combined with Felodipine.Approved, Investigational
FentanylThe serum concentration of Grazoprevir can be increased when it is combined with Fentanyl.Approved, Illicit, Investigational, Vet Approved
FexofenadineThe serum concentration of Grazoprevir can be increased when it is combined with Fexofenadine.Approved
FidaxomicinThe serum concentration of Grazoprevir can be increased when it is combined with Fidaxomicin.Approved
FluconazoleThe serum concentration of Grazoprevir can be increased when it is combined with Fluconazole.Approved
FluoxetineThe serum concentration of Grazoprevir can be increased when it is combined with Fluoxetine.Approved, Vet Approved
FlupentixolThe serum concentration of Grazoprevir can be increased when it is combined with Flupentixol.Approved, Withdrawn
FluphenazineThe serum concentration of Grazoprevir can be increased when it is combined with Fluphenazine.Approved
FlurazepamThe serum concentration of Grazoprevir can be increased when it is combined with Flurazepam.Approved, Illicit
FluvoxamineThe serum concentration of Grazoprevir can be increased when it is combined with Fluvoxamine.Approved, Investigational
GefitinibThe serum concentration of Grazoprevir can be increased when it is combined with Gefitinib.Approved, Investigational
GenisteinThe serum concentration of Grazoprevir can be increased when it is combined with Genistein.Investigational
GlyburideThe serum concentration of Grazoprevir can be increased when it is combined with Glyburide.Approved
Gramicidin DThe serum concentration of Grazoprevir can be increased when it is combined with Gramicidin D.Approved
GrepafloxacinThe serum concentration of Grazoprevir can be increased when it is combined with Grepafloxacin.Withdrawn
HaloperidolThe serum concentration of Grazoprevir can be increased when it is combined with Haloperidol.Approved
HydrocortisoneThe serum concentration of Grazoprevir can be increased when it is combined with Hydrocortisone.Approved, Vet Approved
IdelalisibThe serum concentration of Grazoprevir can be increased when it is combined with Idelalisib.Approved
ImatinibThe serum concentration of Grazoprevir can be increased when it is combined with Imatinib.Approved
ImipramineThe serum concentration of Grazoprevir can be increased when it is combined with Imipramine.Approved
IndinavirThe serum concentration of Grazoprevir can be decreased when it is combined with Indinavir.Approved
IndomethacinThe serum concentration of Grazoprevir can be increased when it is combined with Indomethacin.Approved, Investigational
IsavuconazoniumThe serum concentration of Grazoprevir can be increased when it is combined with Isavuconazonium.Approved, Investigational
ItraconazoleThe serum concentration of Grazoprevir can be increased when it is combined with Itraconazole.Approved, Investigational
IvacaftorThe serum concentration of Grazoprevir can be increased when it is combined with Ivacaftor.Approved
IvermectinThe serum concentration of Grazoprevir can be increased when it is combined with Ivermectin.Approved, Vet Approved
KetamineThe serum concentration of Grazoprevir can be increased when it is combined with Ketamine.Approved, Vet Approved
KetoconazoleThe serum concentration of Grazoprevir can be increased when it is combined with Ketoconazole.Approved, Investigational
LansoprazoleThe serum concentration of Grazoprevir can be increased when it is combined with Lansoprazole.Approved, Investigational
LapatinibThe serum concentration of Grazoprevir can be increased when it is combined with Lapatinib.Approved, Investigational
LevofloxacinThe serum concentration of Grazoprevir can be increased when it is combined with Levofloxacin.Approved, Investigational
LevothyroxineThe serum concentration of Grazoprevir can be decreased when it is combined with Levothyroxine.Approved
LidocaineThe serum concentration of Grazoprevir can be increased when it is combined with Lidocaine.Approved, Vet Approved
LiothyronineThe serum concentration of Grazoprevir can be decreased when it is combined with Liothyronine.Approved, Vet Approved
LiotrixThe serum concentration of Grazoprevir can be decreased when it is combined with Liotrix.Approved
LisinoprilThe serum concentration of Grazoprevir can be increased when it is combined with Lisinopril.Approved, Investigational
LomitapideThe serum concentration of Grazoprevir can be increased when it is combined with Lomitapide.Approved
LoperamideThe serum concentration of Grazoprevir can be increased when it is combined with Loperamide.Approved
LopinavirThe serum concentration of Grazoprevir can be increased when it is combined with Lopinavir.Approved
LoratadineThe serum concentration of Grazoprevir can be increased when it is combined with Loratadine.Approved
LosartanThe serum concentration of Grazoprevir can be increased when it is combined with Losartan.Approved
LovastatinThe serum concentration of Grazoprevir can be increased when it is combined with Lovastatin.Approved, Investigational
LumacaftorThe serum concentration of Grazoprevir can be decreased when it is combined with Lumacaftor.Approved
MaprotilineThe serum concentration of Grazoprevir can be increased when it is combined with Maprotiline.Approved
MebendazoleThe serum concentration of Grazoprevir can be increased when it is combined with Mebendazole.Approved, Vet Approved
MefloquineThe serum concentration of Grazoprevir can be increased when it is combined with Mefloquine.Approved
Megestrol acetateThe serum concentration of Grazoprevir can be increased when it is combined with Megestrol acetate.Approved, Vet Approved
MeprobamateThe serum concentration of Grazoprevir can be increased when it is combined with Meprobamate.Approved, Illicit
MethadoneThe serum concentration of Grazoprevir can be increased when it is combined with Methadone.Approved
MetoprololThe serum concentration of Grazoprevir can be increased when it is combined with Metoprolol.Approved, Investigational
MibefradilThe serum concentration of Grazoprevir can be increased when it is combined with Mibefradil.Withdrawn
MiconazoleThe serum concentration of Grazoprevir can be increased when it is combined with Miconazole.Approved, Investigational, Vet Approved
MidazolamThe serum concentration of Grazoprevir can be decreased when it is combined with Midazolam.Approved, Illicit
MifepristoneThe serum concentration of Grazoprevir can be decreased when it is combined with Mifepristone.Approved, Investigational
MitomycinThe serum concentration of Grazoprevir can be increased when it is combined with Mitomycin.Approved
MitoxantroneThe serum concentration of Grazoprevir can be decreased when it is combined with Mitoxantrone.Approved, Investigational
MorphineThe serum concentration of Grazoprevir can be increased when it is combined with Morphine.Approved, Investigational
NaltrexoneThe serum concentration of Grazoprevir can be increased when it is combined with Naltrexone.Approved, Investigational, Vet Approved
NaringeninThe serum concentration of Grazoprevir can be increased when it is combined with Naringenin.Experimental
NefazodoneThe serum concentration of Grazoprevir can be decreased when it is combined with Nefazodone.Approved, Withdrawn
NelfinavirThe serum concentration of Grazoprevir can be decreased when it is combined with Nelfinavir.Approved
NeostigmineThe serum concentration of Grazoprevir can be increased when it is combined with Neostigmine.Approved, Vet Approved
NicardipineThe serum concentration of Grazoprevir can be increased when it is combined with Nicardipine.Approved
NifedipineThe serum concentration of Grazoprevir can be decreased when it is combined with Nifedipine.Approved
NilotinibThe serum concentration of Grazoprevir can be increased when it is combined with Nilotinib.Approved, Investigational
NisoldipineThe serum concentration of Grazoprevir can be increased when it is combined with Nisoldipine.Approved
NitrazepamThe serum concentration of Grazoprevir can be increased when it is combined with Nitrazepam.Approved
NitrendipineThe serum concentration of Grazoprevir can be increased when it is combined with Nitrendipine.Approved
NorethisteroneThe serum concentration of Grazoprevir can be decreased when it is combined with Norethisterone.Approved
OmeprazoleThe serum concentration of Grazoprevir can be increased when it is combined with Omeprazole.Approved, Investigational, Vet Approved
P-NitrophenolThe serum concentration of Grazoprevir can be increased when it is combined with P-Nitrophenol.Experimental
PaclitaxelThe serum concentration of Grazoprevir can be increased when it is combined with Paclitaxel.Approved, Vet Approved
Palmitic AcidThe serum concentration of Grazoprevir can be increased when it is combined with Palmitic Acid.Experimental
PantoprazoleThe serum concentration of Grazoprevir can be increased when it is combined with Pantoprazole.Approved
ParoxetineThe serum concentration of Grazoprevir can be increased when it is combined with Paroxetine.Approved, Investigational
PerindoprilThe serum concentration of Grazoprevir can be increased when it is combined with Perindopril.Approved
PhenobarbitalThe serum concentration of Grazoprevir can be decreased when it is combined with Phenobarbital.Approved
PimozideThe serum concentration of Grazoprevir can be increased when it is combined with Pimozide.Approved
Platelet Activating FactorThe serum concentration of Grazoprevir can be decreased when it is combined with Platelet Activating Factor.Experimental
PonatinibThe serum concentration of Grazoprevir can be increased when it is combined with Ponatinib.Approved
PosaconazoleThe serum concentration of Grazoprevir can be increased when it is combined with Posaconazole.Approved, Investigational, Vet Approved
PravastatinThe serum concentration of Grazoprevir can be increased when it is combined with Pravastatin.Approved
PrazosinThe serum concentration of Grazoprevir can be increased when it is combined with Prazosin.Approved
PrednisoneThe serum concentration of Grazoprevir can be increased when it is combined with Prednisone.Approved, Vet Approved
ProbenecidThe serum concentration of Grazoprevir can be increased when it is combined with Probenecid.Approved
ProgesteroneThe serum concentration of Grazoprevir can be decreased when it is combined with Progesterone.Approved, Vet Approved
PromethazineThe serum concentration of Grazoprevir can be increased when it is combined with Promethazine.Approved
PropafenoneThe serum concentration of Grazoprevir can be increased when it is combined with Propafenone.Approved
PropranololThe serum concentration of Grazoprevir can be increased when it is combined with Propranolol.Approved, Investigational
ProtriptylineThe serum concentration of Grazoprevir can be increased when it is combined with Protriptyline.Approved
QuercetinThe serum concentration of Grazoprevir can be increased when it is combined with Quercetin.Experimental
QuinacrineThe serum concentration of Grazoprevir can be increased when it is combined with Quinacrine.Approved
QuinidineThe serum concentration of Grazoprevir can be increased when it is combined with Quinidine.Approved
QuinineThe serum concentration of Grazoprevir can be increased when it is combined with Quinine.Approved
RanitidineThe serum concentration of Grazoprevir can be increased when it is combined with Ranitidine.Approved
RanolazineThe serum concentration of Grazoprevir can be increased when it is combined with Ranolazine.Approved, Investigational
ReboxetineThe serum concentration of Grazoprevir can be increased when it is combined with Reboxetine.Approved, Investigational
RegorafenibThe serum concentration of Grazoprevir can be increased when it is combined with Regorafenib.Approved
ReserpineThe serum concentration of Grazoprevir can be decreased when it is combined with Reserpine.Approved
RifampicinThe serum concentration of Grazoprevir can be decreased when it is combined with Rifampicin.Approved
RilpivirineThe serum concentration of Grazoprevir can be increased when it is combined with Rilpivirine.Approved
RitonavirThe serum concentration of Grazoprevir can be decreased when it is combined with Ritonavir.Approved, Investigational
RolapitantThe serum concentration of Grazoprevir can be increased when it is combined with Rolapitant.Approved
SaquinavirThe serum concentration of Grazoprevir can be decreased when it is combined with Saquinavir.Approved, Investigational
ScopolamineThe serum concentration of Grazoprevir can be increased when it is combined with Scopolamine.Approved
SelegilineThe serum concentration of Grazoprevir can be increased when it is combined with Selegiline.Approved, Investigational, Vet Approved
SertralineThe serum concentration of Grazoprevir can be increased when it is combined with Sertraline.Approved
SimeprevirThe serum concentration of Grazoprevir can be increased when it is combined with Simeprevir.Approved
SimvastatinThe serum concentration of Grazoprevir can be increased when it is combined with Simvastatin.Approved
SirolimusThe serum concentration of Grazoprevir can be decreased when it is combined with Sirolimus.Approved, Investigational
SorafenibThe serum concentration of Grazoprevir can be increased when it is combined with Sorafenib.Approved, Investigational
SpironolactoneThe serum concentration of Grazoprevir can be increased when it is combined with Spironolactone.Approved
St. John's WortThe serum concentration of Grazoprevir can be decreased when it is combined with St. John&#39;s Wort.Nutraceutical
StaurosporineThe serum concentration of Grazoprevir can be increased when it is combined with Staurosporine.Experimental
StreptozocinThe serum concentration of Grazoprevir can be decreased when it is combined with Streptozocin.Approved
SulfinpyrazoneThe serum concentration of Grazoprevir can be increased when it is combined with Sulfinpyrazone.Approved
SumatriptanThe serum concentration of Grazoprevir can be increased when it is combined with Sumatriptan.Approved, Investigational
SunitinibThe serum concentration of Grazoprevir can be increased when it is combined with Sunitinib.Approved, Investigational
TacrineThe serum concentration of Grazoprevir can be increased when it is combined with Tacrine.Withdrawn
TacrolimusThe serum concentration of Grazoprevir can be decreased when it is combined with Tacrolimus.Approved, Investigational
TamoxifenThe serum concentration of Grazoprevir can be decreased when it is combined with Tamoxifen.Approved
Taurocholic AcidThe serum concentration of Grazoprevir can be increased when it is combined with Taurocholic Acid.Experimental
TelmisartanThe serum concentration of Grazoprevir can be increased when it is combined with Telmisartan.Approved, Investigational
TemsirolimusThe serum concentration of Grazoprevir can be increased when it is combined with Temsirolimus.Approved
TerazosinThe serum concentration of Grazoprevir can be increased when it is combined with Terazosin.Approved
TerfenadineThe serum concentration of Grazoprevir can be increased when it is combined with Terfenadine.Withdrawn
TeriflunomideThe serum concentration of Grazoprevir can be increased when it is combined with Teriflunomide.Approved
TesmilifeneThe serum concentration of Grazoprevir can be decreased when it is combined with Tesmilifene.Investigational
TestosteroneThe serum concentration of Grazoprevir can be increased when it is combined with Testosterone.Approved, Investigational
TicagrelorThe serum concentration of Grazoprevir can be increased when it is combined with Ticagrelor.Approved
TolvaptanThe serum concentration of Grazoprevir can be increased when it is combined with Tolvaptan.Approved
TrazodoneThe serum concentration of Grazoprevir can be decreased when it is combined with Trazodone.Approved, Investigational
TrifluoperazineThe serum concentration of Grazoprevir can be increased when it is combined with Trifluoperazine.Approved
TriflupromazineThe serum concentration of Grazoprevir can be increased when it is combined with Triflupromazine.Approved, Vet Approved
TrimethoprimThe serum concentration of Grazoprevir can be decreased when it is combined with Trimethoprim.Approved, Vet Approved
TrimipramineThe serum concentration of Grazoprevir can be increased when it is combined with Trimipramine.Approved
VenlafaxineThe serum concentration of Grazoprevir can be increased when it is combined with Venlafaxine.Approved
VerapamilThe serum concentration of Grazoprevir can be decreased when it is combined with Verapamil.Approved
VinblastineThe serum concentration of Grazoprevir can be decreased when it is combined with Vinblastine.Approved
VincristineThe serum concentration of Grazoprevir can be decreased when it is combined with Vincristine.Approved, Investigational
VinorelbineThe serum concentration of Grazoprevir can be increased when it is combined with Vinorelbine.Approved, Investigational
ZimelidineThe serum concentration of Grazoprevir can be increased when it is combined with Zimelidine.Withdrawn
Food Interactions
  • Relative to fasting conditions, the administration of a single dose of grazoprevir + elbasvir (Zapatier) with a high-fat (900 kcal, 500 kcal from fat) meal to healthy subjects resulted in decreases in elbasvir AUC0-inf and Cmax of approximately 11% and 15%, respectively, and increases in grazoprevir AUC0-inf and Cmax of approximately 1.5-fold and 2.8-fold, respectively.
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]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (441 KB)
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentChronic Hepatitis C Infection / Transplant, Kidney1
1CompletedTreatmentChronic Hepatitis C Infection3
1CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Impaired Renal Function1
1WithdrawnDiagnosticChronic Hepatitis C Virus (HCV) Infection1
1, 2RecruitingTreatmentEnd Stage Renal Disease (ESRD)1
1, 2RecruitingTreatmentHeart Failure, Unspecified1
2CompletedTreatmentChronic Hepatitis C Infection8
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
2CompletedTreatmentHepatitis C Virus (HCV)1
2CompletedTreatmentHepatitis C, Chronic1
2RecruitingTreatmentAcute Hepatitis C / HIV Disease1
2TerminatedTreatmentHepatitis C, Chronic1
2, 3CompletedTreatmentChronic Hepatitis C Infection1
2, 3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
2, 3CompletedTreatmentHepatitis C Virus (HCV)1
3CompletedTreatmentChronic Hepatitis C Infection2
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection1
3CompletedTreatmentHepatitis C Infection1
3Not Yet RecruitingTreatmentChronic HCV Infection1
3Not Yet RecruitingTreatmentChronic Hepatitis C Infection / HIV Disease1
3Not Yet RecruitingTreatmentChronic Hepatitis C Infection / Transplantation, Liver1
3Not Yet RecruitingTreatmentChronic Hepatitis C Infection / Compensated liver disease1
3Not Yet RecruitingTreatmentChronic hepatitis C genotype 1b / Cirrhoses, Liver / Fibrosis, Liver / Metabolic Syndromes1
3RecruitingTreatmentAcute Hepatitis C / Chronic Hepatitis C Infection / Human Immunodeficiency Virus (HIV)1
3RecruitingTreatmentHepatitis C, Chronic1
3WithdrawnTreatmentChronic Hepatitis C Infection1
4Active Not RecruitingTreatmentChronic Hepatitis C Infection / End-Stage Renal Disease (ESRD)1
4Enrolling by InvitationTreatmentChronic Hepatitis C Infection / Substance Abuse, Intravenous / Substance Use Disorder (SUD)1
4Not Yet RecruitingPreventionCardiac Transplant Disorder / Chronic Hepatitis C Infection1
4Not Yet RecruitingPreventionChronic Hepatitis C Infection / Renal Failure Chronic1
4Not Yet RecruitingTreatmentChronic Hepatitis C Infection2
4Not Yet RecruitingTreatmentTo Assess the Efficacy of Grazoprevir 100mg and Elbasvir 50mg by Determining the Proportion of Sustained Virological Response 12 Weeks After the End of Therapy1
4RecruitingPreventionRenal Failure1
4RecruitingTreatmentChronic Hepatitis C Infection1
4RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection2
4WithdrawnTreatmentHCV1
Not AvailableEnrolling by InvitationNot AvailableChronic Hepatitis C Infection1
Not AvailableNot Yet RecruitingTreatmentHCV, HCC1
Not AvailableRecruitingNot AvailableChronic Hepatitis C Infection1
Not AvailableRecruitingNot AvailableHepatitis C, Chronic / Human Immunodeficiency Virus (HIV)1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8871759 No2011-05-042031-05-04Us
US7973040 No2009-07-242029-07-24Us
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0097 mg/mLALOGPS
logP3.14ALOGPS
logP5.41ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)5.31ChemAxon
pKa (Strongest Basic)1.81ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count14ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area205.69 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity195.25 m3·mol-1ChemAxon
Polarizability81.09 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET featuresNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as cyclic peptides. These are compounds containing a cyclic moiety bearing a peptide backbone.
KingdomChemical entities
Super ClassOrganic compounds
ClassOrganic acids and derivatives
Sub ClassCarboxylic acids and derivatives
Direct ParentCyclic peptides
Alternative ParentsMacrolactams / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Quinoxalines / Pyrrolidinecarboxamides / Anisoles / Alkyl aryl ethers / Pyrazines / Cyclopropanecarboxylic acids and derivatives / Tertiary carboxylic acid amides
SubstituentsCyclic alpha peptide / Macrolactam / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Diazanaphthalene / Alpha-amino acid or derivatives / Quinoxaline / Anisole / Pyrrolidine carboxylic acid or derivatives / Pyrrolidine-2-carboxamide
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot 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
Human
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Uniprot Name:
Cytochrome P450 3A4
Molecular Weight:
57342.67 Da

Carriers

Kind
Protein
Organism
Human
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 colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
Gene Name:
ALB
Uniprot ID:
P02768
Uniprot Name:
Serum albumin
Molecular Weight:
69365.94 Da
Kind
Protein
Organism
Human
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 the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
Gene Name:
ORM1
Uniprot ID:
P02763
Uniprot Name:
Alpha-1-acid glycoprotein 1
Molecular Weight:
23511.38 Da

Transporters

Kind
Protein
Organism
Human
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
Human
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, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:
SLCO1B1
Uniprot ID:
Q9Y6L6
Uniprot Name:
Solute carrier organic anion transporter family member 1B1
Molecular Weight:
76447.99 Da
Kind
Protein
Organism
Human
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), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver.
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 September 01, 2017 12:10