Identification
- Name
- Glecaprevir
- Accession Number
- DB13879
- Type
- Small Molecule
- Groups
- Approved, Investigational
- 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 [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 [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 [Label].
- Structure
Structure for Glecaprevir (DB13879)
- 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
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Maviret Glecaprevir (100 mg) + Pibrentasvir (40 mg) Tablet Oral Abbvie 2017-09-13 Not applicable Canada 
Mavyret Glecaprevir (100 mg/1) + Pibrentasvir (40 mg/1) Tablet, film coated Oral Abbvie 2017-08-03 Not applicable US 
- Categories
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Breast Cancer Resistance Protein Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P450 1A2 Inhibitors
- Cytochrome P450 3A Inhibitors
- HCV NS3/4A Protease Inhibitors
- NS3/4A Protease Inhibitors
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B1/SLCO1B1 Substrates
- OATP1B3 transporter inhibitors
- Organic Anion Transporting Polypeptide 1B1 Inhibitors
- Organic Anion Transporting Polypeptide 1B3 Inhibitors
- P-glycoprotein/ABCB1 Inhibitors
- P-glycoprotein/ABCB1 Substrates
- UGT1A1 Inhibitors
- 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)[C@@H]1NC(=O)O[C@@H]2CCC[C@H]2OC\C=C\C(F)(F)C2=NC3=C(C=CC=C3)N=C2O[C@@H]2C[C@H](N(C2)C1=O)C(=O)N[C@@]1(C[C@H]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 [Label].
- Associated Conditions
- Chronic Hepatitis C Genotype 1
- Chronic hepatitis C genotype 2
- Chronic hepatitis C genotype 3
- Chronic hepatitis C genotype 4
- Chronic hepatitis C genotype 5
- Genotype 6 chronic hepatitis C infection
- Previously treated with an HCV regimen containing an NS3/4A protease inhibitor Chronic Hepatitis C Genotype 1
- Previously treated with an HCV regimen containing an NS5A inhibitor Chronic Hepatitis C Genotype 1
- 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 [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 [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].
Target Actions Organism ANS3 protease inhibitorHepatitis 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% [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 [Label].
- Metabolism
Glecaprevir undergoes limited secondary metabolism in vitro, predominantly by CYP3A [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 [Label].
- Half life
The elimination half life (t1/2) is approximately 6 hours [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 [Label].
- Affected organisms
- Hepatitis C Virus
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction Acebutolol The serum concentration of Acebutolol can be increased when it is combined with Glecaprevir. Acetaminophen The serum concentration of Glecaprevir can be increased when it is combined with Acetaminophen. Acetylsalicylic acid The serum concentration of Acetylsalicylic acid can be increased when it is combined with Glecaprevir. Afatinib The serum concentration of Afatinib can be increased when it is combined with Glecaprevir. Amiodarone The serum concentration of Glecaprevir can be increased when it is combined with Amiodarone. Amitriptyline The serum concentration of Amitriptyline can be increased when it is combined with Glecaprevir. Amlodipine The serum concentration of Glecaprevir can be increased when it is combined with Amlodipine. Amsacrine The serum concentration of Glecaprevir can be increased when it is combined with Amsacrine. Apalutamide The serum concentration of Glecaprevir can be decreased when it is combined with Apalutamide. Ascorbic acid The serum concentration of Ascorbic acid can be increased when it is combined with Glecaprevir. - Food Interactions
- Not Available
References
- General References
- 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]
- 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
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Tablet Oral Tablet, film coated Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) US9586978 No 2010-06-10 2030-06-10 US US8648037 No 2012-01-19 2032-01-19 US US9321807 No 2015-06-05 2035-06-05 US US8937150 No 2012-05-18 2032-05-18 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility <0.1 to 0.3 mg/mL FDA Label - Predicted Properties
Property Value Source Water Solubility 0.0463 mg/mL ALOGPS logP 4.26 ALOGPS logP 3.95 ChemAxon logS -4.3 ALOGPS pKa (Strongest Acidic) 3.74 ChemAxon pKa (Strongest Basic) -1.2 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 10 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 195.22 Å2 ChemAxon Rotatable Bond Count 6 ChemAxon Refractivity 194.55 m3·mol-1 ChemAxon Polarizability 80.16 Å3 ChemAxon Number of Rings 7 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - 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
- SubstrateInhibitor
- 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
- SubstrateInhibitor
- 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
- SubstrateInhibitor
- 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
- SubstrateInhibitor
- 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
- SubstrateInhibitor
- 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 August 02, 2018 07:00