Identification

Name
Glecaprevir
Accession Number
DB13879
Type
Small Molecule
Groups
Approved
Description

Glecaprevir is a direct acting antiviral agent and Hepatitis C virus (HCV) NS3/4A protease inhibitor that targets the the viral RNA replication. In combination with Pibrentasvir, glecaprevir is a useful therapy for patients who experienced therapeutic failure from other NS3/4A protease inhibitors. It demonstrates a high genetic barrier against resistance mutations of the virus. In cell cultures, the emergence of amino acid substitutions at NS3 resistance-associated positions A156 or D/Q168 in HCV genotype 1a, 2a or 3a replicons led to reduced susceptibility to glecaprevir [FDA Label]. The combinations of amino acid substitutions at NS3 position Y65H and D/Q168 also results in greater reductions in glecaprevir susceptibility, and NS3 Q80R in genotype 3a patients also leads to glecaprevir resistance [FDA Label].

Glecaprevir is available as an oral combination therapy with Pibrentasvir under the brand name Mavyret. This fixed-dose combination therapy was FDA-approved in August 2017 to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis [2]. Mavyret is also indicated for HCV genotype 1-infected patients who have been previously treated with regimens either containing an NS5A inhibitor or an NS3/4A protease inhibitor, but not both [2]. Hepatitis C viral infection often leads to decreased liver function and subsequent liver failure, causing a significantly negative impact on the patients' quality of life. The ultimate goal of the combination treatment is to achieve sustained virologic response (SVR) and cure the patients from the infection. In clinical trials, this combination therapy achieved SVR12 rate, or undetectable Hepatitis C for twelve or more weeks after the end of treatment, of ≥93% across genotypes 1a, 2a, 3a, 4, 5 and 6 [FDA Label].

Structure
Thumb
Synonyms
  • (3aR,7S,10S,12R,21E,24aR)-7-tert-butyl-N-{(1R,2R)-2­ (difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl}-20,20-difluoro­ 5,8-dioxo-2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1H,10H-9,12­ methanocyclopenta[18,19][1,10,17,3,6]trioxadiazacyclononadecino[11,12-b]quinoxaline-10­ carboxamide hydrate
  • Glécaprévir
  • glecaprevirum
External IDs
A-1282576 / A-1282576.0 / A-12825760 / ABT-493
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
MaviretGlecaprevir (100 mg) + Pibrentasvir (40 mg)TabletOralAbbvie2017-09-13Not applicableCanada
MavyretGlecaprevir (100 mg/1) + Pibrentasvir (40 mg/1)Tablet, film coatedOralAbbvie2017-08-03Not applicableUs
Categories
UNII
K6BUU8J72P
CAS number
1365970-03-1
Weight
Average: 838.87
Monoisotopic: 838.298310911
Chemical Formula
C38H46F4N6O9S
InChI Key
MLSQGNCUYAMAHD-ITNVBOSISA-N
InChI
InChI=1S/C38H46F4N6O9S/c1-35(2,3)28-32(50)48-19-20(17-24(48)30(49)46-37(18-21(37)29(39)40)33(51)47-58(53,54)36(4)14-15-36)56-31-27(43-22-9-5-6-10-23(22)44-31)38(41,42)13-8-16-55-25-11-7-12-26(25)57-34(52)45-28/h5-6,8-10,13,20-21,24-26,28-29H,7,11-12,14-19H2,1-4H3,(H,45,52)(H,46,49)(H,47,51)/b13-8+/t20-,21+,24+,25-,26-,28-,37-/m1/s1
IUPAC Name
(1R,14E,18R,22R,26S,29S)-26-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-13,13-difluoro-24,27-dioxo-2,17,23-trioxa-4,11,25,28-tetraazapentacyclo[26.2.1.0^{3,12}.0^{5,10}.0^{18,22}]hentriaconta-3,5(10),6,8,11,14-hexaene-29-carboxamide
SMILES
CC(C)(C)[[email protected]@H]1NC(=O)O[[email protected]@H]2CCC[[email protected]]2OC\C=C\C(F)(F)C2=NC3=C(C=CC=C3)N=C2O[[email protected]@H]2C[[email protected]](N(C2)C1=O)C(=O)N[[email protected]@]1(C[[email protected]]1C(F)F)C(=O)NS(=O)(=O)C1(C)CC1

Pharmacology

Indication

Indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is also indicated for the treatment of adult patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both [FDA Label].

Structured Indications
Pharmacodynamics

In a biochemical assay studying clinical isolates of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a, glecaprevir displayed IC50 values ranging from 3.5 to 11.3 nM that resulted in inhibition of the proteolytic activity of recombinant NS3/4A enzymes. In HCV replicon assays, glecaprevir had median EC50 values of 0.08-4.6 nM against laboratory and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a [FDA Label]. In a QT study, glecaprevir is not shown to prolong the QTc interval.

Mechanism of action

Glecaprevir is an inhibitor of the HCV NS3/4A protease, which is a viral enzyme necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins [FDA Label]. These multifunctional proteins, including NS3, are essential for viral replication. The N-terminal of NS3 protein confers serine protease activity, whileThe C-terminus of NS3 encodes a DExH/D-box RNA helicase which hydyolyzes NTP as an energy source to unwind double-stranded RNA in a 3′ to 5′ direction during replication of viral genomic RNA [1]. NS4A is a cofactor for NS3 that directs the localization of NS3 and modulates its enzymatic activities [1]. Glecaprevir disrupts the intracellular processes of the viral life cycle through inhibiting the NS3/4A protease activity of cleaving downstream junctions of HCV polypeptide and proteolytic processing of mature structural proteins [1].

TargetActionsOrganism
ANS3 protease
inhibitor
Hepatitis C virus
Absorption

In healthy subjects, the time it takes to reach the peak plasma concentration (Tmax) is approximately 5 hours. The mean peak plasma concentration (Cmax) is 597ng/mL in non-cirrhotic HCV-infected subjects. Relative to fasting conditions, the consumption of meals increases the absorption of glecaprevir by 83-163% [FDA Label].

Volume of distribution
Not Available
Protein binding

Pibrentasvir is 97.5% bound to human plasma proteins. The Blood-to-plasma ratio is approximately 0.57 [FDA Label].

Metabolism

Glecaprevir undergoes limited secondary metabolism in vitro, predominantly by CYP3A [FDA Label].

Route of elimination

The predominant route of elimination of the drug is biliary-fecal, where 92.1% of administered drug is excreted in feces and 0.7% of the drug is excreted in the urine [FDA Label].

Half life

The elimination half life (t1/2) is approximately 6 hours [FDA Label].

Clearance
Not Available
Toxicity

Glecaprevir is not shown to be genotoxic according to in vitro or in vivo studies. It also shows to have no effect on mating, female or male fertility, or early embryonic development in rodent studies. Carcinogenicity studies with glecaprevir have not been conducted [FDA Label].

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

Interactions

Drug Interactions
DrugInteractionDrug group
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Glecaprevir.Approved
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Glecaprevir.Approved
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Glecaprevir.Approved
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Glecaprevir.Approved
Dabigatran etexilateThe serum concentration of the active metabolites of Dabigatran etexilate can be increased when Dabigatran etexilate is used in combination with Glecaprevir.Approved
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Glecaprevir.Approved, Investigational
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Glecaprevir.Approved
EltrombopagThe serum concentration of Glecaprevir can be increased when it is combined with Eltrombopag.Approved
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Glecaprevir.Approved
IrinotecanThe serum concentration of SN-38 an active metabolite of Irinotecan can be increased when used in combination with Glecaprevir.Approved, Investigational
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Glecaprevir.Approved
LumacaftorThe serum concentration of Glecaprevir can be decreased when it is combined with Lumacaftor.Approved
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Glecaprevir.Approved
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Glecaprevir.Approved
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Glecaprevir.Approved
RanolazineThe serum concentration of Ranolazine can be increased when it is combined with Glecaprevir.Approved, Investigational
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Glecaprevir.Approved, Investigational
RolapitantThe serum concentration of Glecaprevir can be increased when it is combined with Rolapitant.Approved
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Glecaprevir.Approved
TeriflunomideThe serum concentration of Glecaprevir can be increased when it is combined with Teriflunomide.Approved
TizanidineThe serum concentration of Tizanidine can be increased when it is combined with Glecaprevir.Approved
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Glecaprevir.Approved, Investigational
VincristineThe serum concentration of Vincristine can be increased when it is combined with Glecaprevir.Approved, Investigational
Food Interactions
Not Available

References

General References
  1. Salam KA, Akimitsu N: Hepatitis C virus NS3 inhibitors: current and future perspectives. Biomed Res Int. 2013;2013:467869. doi: 10.1155/2013/467869. Epub 2013 Oct 27. [PubMed:24282816]
  2. FDA Press Announcements: FDA approves Mavyret for Hepatitis C [Link]
External Links
KEGG Drug
D10814
PubChem Compound
66828839
PubChem Substance
347829330
ChemSpider
35013015
ChEMBL
CHEMBL3545363
Wikipedia
Glecaprevir
FDA label
Download (925 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHepatic Impairment1
1CompletedBasic ScienceImpaired Renal Function1
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / HCV / Hepatitis C Virus (HCV)2
2CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Compensated liver disease / Hepatitis C Virus (HCV)1
2Enrolling by InvitationDiagnosticChronic Hepatitis C Infection1
2, 3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Hepatitis C Virus (HCV)1
3Active Not RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection / Compensated Cirrhosis and Non-cirrhotics / Hepatitis C Virus Infection / Human Immunodeficiency Virus (HIV) Infections1
3Active Not RecruitingTreatmentChronic Hepatitis C Virus / Hepatitis C Virus (HCV)1
3Active Not RecruitingTreatmentHepatitis C Virus (HCV)1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection2
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Genotype 3 Hepatitis C Virus / Hepatitis C Virus (HCV)1
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / HCV / Hepatitis C Virus (HCV)2
3CompletedTreatmentChronic Hepatitis C Virus (HCV) Infection / Compensated liver disease / Hepatitis C Virus Infection1
3CompletedTreatmentChronic Hepatitis C Virus / Hepatitis C Virus (HCV)1
3CompletedTreatmentHepatitis C Virus (HCV)1
3Enrolling by InvitationTreatmentHepatitis C Virus Infection1
3Not Yet RecruitingTreatmentHepatitis C Virus (HCV)1
3RecruitingTreatmentChronic Hepatitis C Infection / HCV1
3RecruitingTreatmentChronic Hepatitis C Virus (HCV) Genotype 5 or 6 Infection1
3RecruitingTreatmentChronic Hepatitis C Virus (HCV) Infection1
3RecruitingTreatmentHepatitis C Virus (HCV)4
3RecruitingTreatmentHepatitis C, Acute1
Not AvailableAvailableNot AvailableHepatitis C Virus Infection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<0.1 to 0.3 mg/mLFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0463 mg/mLALOGPS
logP4.26ALOGPS
logP3.95ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)3.74ChemAxon
pKa (Strongest Basic)-1.2ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area195.22 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity194.55 m3·mol-1ChemAxon
Polarizability80.16 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
Not Available

Taxonomy

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 / Alkyl aryl ethers / Pyrazines / Benzenoids / Cyclopropanecarboxylic acids and derivatives / Tertiary carboxylic acid amides
show 16 more
Substituents
Cyclic alpha peptide / Macrolactam / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Diazanaphthalene / Alpha-amino acid or derivatives / Quinoxaline / Pyrrolidine carboxylic acid or derivatives / Pyrrolidine-2-carboxamide / Alkyl aryl ether
show 33 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Hepatitis C virus
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type peptidase activity
Specific Function
Not Available
Gene Name
Not Available
Uniprot ID
Q91RS4
Uniprot Name
NS3 protease
Molecular Weight
19113.77 Da

Enzymes

Kind
Protein group
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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...

Components:
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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 August 31, 2017 09:33 / Updated on December 01, 2017 16:46