Grazoprevir

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Grazoprevir
Grazoprevir.svg
Clinical data
Trade names Zepatier (combination with elbasvir)
Other namesMK-5172
License data
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 98.8%
Metabolism CYP3A4
Elimination half-life 31 hours
Excretion >90% via faeces, <1% via urine
Identifiers
  • (1R,18R,20R,24S,27S)-N-{(1R,2S)-1-[(Cyclopropylsulfonyl)carbamoyl]-2-vinylcyclopropyl}-7-methoxy-24-(2-methyl-2-propanyl)-22,25-dioxo-2,21-dioxa-4,11,23,26-tetraazapentacyclo[24.2.1.03,12.05,10.0 18,20]nonacosa-3,5,7,9,11-pentaene-27-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
Formula C38H50N6O9S
Molar mass 766.91 g·mol−1
3D model (JSmol)
    • O=C1C(C(C)(C)C)NC(=O)OC3CC3CCCCCc2nc4ccc(OC)cc4nc2OC(C6)CN1C6C(=O)NC5(CC5C=C)C(=O)NS(=O)(=O)C7CC7
    • 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
    • Key:OBMNJSNZOWALQB-NCQNOWPTSA-N

    Grazoprevir is a drug [1] approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier , either with or without ribavirin. [2]

    Contents

    Grazoprevir is a second generation hepatitis C virus protease inhibitor acting at the NS3/4A protease targets. [3] It has good activity against a range of HCV genotype variants, including some that are resistant to most currently used antiviral medications. [4] [5]

    Side effects

    Side effects have only been assessed in the combination with elbasvir. Common side effects of the combination include feeling tired, nausea, reduced appetite, and headache. Low red blood cell count has occurred when co-administered with ribavirin in some cases. [6] [7] The most important risks are alanine transaminase elevation, hyperbilirubinemia, drug resistance development and drug interactions. [8]

    Interactions

    Grazoprevir is transported by the solute carrier proteins SLCO1B1 and SLCO1B3. Drugs that inhibit this proteins, such as rifampicin, ciclosporin, and a number of AIDS medications (atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cobicistat), can cause a significant increase in grazoprevir blood plasma levels. The substance is degraded by the liver enzyme CYP3A4. Combination with drugs that induce this enzyme, such as efavirenz, carbamazepine or St. John's wort, can lead to ineffectively low plasma levels of grazoprevir. Combination with CYP3A4 inhibitors may increase plasma levels. [7] [9]

    Pharmacology

    Mechanism of action

    Grazoprevir blocks NS3, a serine protease enzyme the virus needs for splitting its polyprotein into the functional virus proteins, and NS4A, a cofactor of NS3. [7]

    Pharmacokinetics

    Grazoprevir reaches peak plasma concentrations two hours after oral intake together with elbasvir (variation between patients: 30 minutes to three hours). In hepatitis C patients, steady state concentrations are found after about six days. Plasma protein binding is 98.8%, mainly to albumin and alpha-1-acid glycoprotein. Part of the substance is oxidised in the liver, largely by the enzyme CYP3A4. The biological half-life is 31 hours on average. Over 90% are excreted via the faeces, and less than 1% via the urine. [7]

    Related Research Articles

    Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

    <span class="mw-page-title-main">Hepatitis C virus</span> Species of virus

    The hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.

    <span class="mw-page-title-main">Boceprevir</span> Chemical compound

    Boceprevir is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.

    <span class="mw-page-title-main">Telaprevir</span> Chemical compound

    Telaprevir (VX-950), marketed under the brand names Incivek and Incivo, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex Pharmaceuticals and Johnson & Johnson. It is a member of a class of antiviral drugs known as protease inhibitors. Specifically, telaprevir inhibits the hepatitis C viral enzyme NS3/4A serine protease. Telaprevir is only indicated for use against hepatitis C genotype 1 viral infections and has not been proven to be safe or effective when used for other genotypes of the virus. The standard therapy of pegylated interferon and ribavirin is less effective than telaprevir in those with genotype 1.

    <span class="mw-page-title-main">Ciluprevir</span> Chemical compound

    Ciluprevir was a drug used experimentally in the treatment of hepatitis C. It is manufactured by Boehringer Ingelheim and developed under the research code of BILN 2061. It was the first-in-class NS3/4A protease inhibitor to enter clinical development and tested in human. Ciluprevir is a potent competitive reversible inhibitor of NS3/4A protease from HCV genotype 1a (Ki = 0.3 nM) and 1b (Ki = 0.66 nM). It shows good selectivity for NS3 protease against representative serine and cysteine proteases, human leukocyte elastase and cathepsin B (IC50 > 30 μM).

    <span class="mw-page-title-main">Vaniprevir</span> Chemical compound

    Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) NS3/4A protease inhibitor, developed by Merck & Co., which is currently in clinical testing. In Japan, it was approved for treating hepatitis C in 2014 under the brand name Vanihep.

    <span class="mw-page-title-main">Sofosbuvir</span> Chemical compound

    Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.

    <span class="mw-page-title-main">Asunaprevir</span> Compound

    Asunaprevir is an experimental drug candidate for the treatment of hepatitis C. It was undergoing development by Bristol-Myers Squibb and has completed Phase III clinical trials in 2013.

    <span class="mw-page-title-main">Simeprevir</span> Chemical compound

    Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

    <span class="mw-page-title-main">Paritaprevir</span> Chemical compound

    Paritaprevir is an acylsulfonamide inhibitor of the NS3-4A serine protease manufactured by Abbott Laboratories that shows promising results as a treatment of hepatitis C. When given in combination with ritonavir and ribavirin for 12 weeks, the rate of sustained virologic response at 24 weeks after treatment has been estimated to be 95% for those with hepatitis C virus genotype 1. Resistance to treatment with paritaprevir is uncommon, because it targets the binding site, but has been seen to arise due to mutations at positions 155 and 168 in NS3.

    Ombitasvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection by AbbVie. In the United States, it is approved by the Food and Drug Administration for use in combination with paritaprevir, ritonavir and dasabuvir in the product Viekira Pak for the treatment of HCV genotype 1, and with paritaprevir and ritonavir in the product Technivie for the treatment of HCV genotype 4.

    <span class="mw-page-title-main">Dasabuvir</span> Chemical compound

    Dasabuvir, sold under the brand name Exviera, is an antiviral medication for the treatment of hepatitis C. It is often used together with the combination medication ombitasvir/paritaprevir/ritonavir specifically for hepatitis C virus (HCV) type 1. Ribavirin may also additionally be used. These combinations result in a cure in more than 90% of people. It is taken by mouth.

    <span class="mw-page-title-main">Elbasvir</span> Chemical compound

    Elbasvir is a drug approved by the FDA in January 2016 for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS3/4A protease inhibitor grazoprevir under the trade name Zepatier, either with or without ribavirin.

    Elbasvir/grazoprevir, sold under the brand name Zepatier, is a fixed-dose combination for the treatment of hepatitis C, containing elbasvir and grazoprevir. It is used to treat chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients.

    <span class="mw-page-title-main">Velpatasvir</span> Chemical compound

    Velpatasvir is an NS5A inhibitor which is used together with sofosbuvir in the treatment of hepatitis C infection of all six major genotypes.

    <span class="mw-page-title-main">Narlaprevir</span> Chemical compound

    Narlaprevir, is an inhibitor of NS3/4A serine protease, intended for the treatment of chronic hepatitis C caused by genotype 1 virus in combination with other antiviral drugs.

    <span class="mw-page-title-main">Danoprevir</span> Medication

    Danoprevir (INN) is an orally available 15-membered macrocyclic peptidomimetic inhibitor of NS3/4A HCV protease. It contains acylsulfonamide, fluoroisoindole and tert-butyl carbamate moieties. Danoprevir is a clinical candidate based on its favorable potency profile against multiple HCV genotypes 1–6 and key mutants (GT1b, IC50 = 0.2–0.4 nM; replicon GT1b, EC50 = 1.6 nM). Danoprevir has been evaluated in an open-label, single arm clinical trial in combination with ritonavir for treating COVID-19 and favourably compared to lopinavir/ritonavir in a second trial.

    Sofosbuvir/velpatasvir, sold under the brand name Epclusa among others, is a fixed-dose combination medication for the treatment of hepatitis C in adults. It combines sofosbuvir and velpatasvir. It is more than 90% effective for hepatitis C genotypes one through six. It also works for hepatitis C in those who also have cirrhosis or HIV/AIDS. It is taken by mouth.

    <span class="mw-page-title-main">Glecaprevir/pibrentasvir</span> Combination drug

    Glecaprevir/pibrentasvir (G/P), sold under the brand names Mavyret and Maviret, is a fixed-dose combination medication used to treat hepatitis C. It contains glecaprevir and pibrentasvir. It works against all six types of hepatitis C. At twelve weeks following treatment between 81% and 100% of people have no evidence of hepatitis C. It is taken once a day by mouth with food.

    <span class="mw-page-title-main">NS5B inhibitor</span> Class of pharmaceutical drugs

    Non-structural protein 5B (NS5B) inhibitors are a class of direct-acting antivirals widely used in the treatment of chronic hepatitis C. Depending on site of action and chemical composition, NS5B inhibitors may be categorized into three classes—nucleoside active site inhibitors (NIs), non-nucleoside allosteric inhibitors, and pyrophosphate analogues. Subsequently, all three classes are then subclassified. All inhibit RNA synthesis by NS5B but at different stages/sites resulting in inability of viral RNA replication. Expression of direct-acting NS5B inhibitors does not take place in cells that are not infected by hepatitis C virus, which seems to be beneficial for this class of drugs.

    References

    1. ↑ "FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1 and 4". Food and Drug Administration . 2018-11-03.
    2. ↑ Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, et al. (March 2015). "Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial". Lancet. 385 (9973): 1075–86. doi:10.1016/S0140-6736(14)61795-5. PMID   25467591.
    3. ↑ Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, et al. (April 2012). "Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor". ACS Medicinal Chemistry Letters. 3 (4): 332–6. doi:10.1021/ml300017p. PMC   4025840 . PMID   24900473.
    4. ↑ Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, et al. (August 2012). "MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants". Antimicrobial Agents and Chemotherapy. 56 (8): 4161–7. doi:10.1128/AAC.00324-12. PMC   3421554 . PMID   22615282.
    5. ↑ Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G (May 2014). "MK-5172 : a second-generation protease inhibitor for the treatment of hepatitis C virus infection". Expert Opinion on Investigational Drugs. 23 (5): 719–28. doi:10.1517/13543784.2014.902049. PMID   24666106. S2CID   207477059.
    6. ↑ "ZEPATIER (elbasvir and grazoprevir) Tablets, for Oral Use. Full Prescribing Information" (PDF). Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Retrieved 31 January 2016.
    7. 1 2 3 4 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
    8. ↑ "European Public Assessment Report" (PDF). European Medicines Agency. Archived from the original (PDF) on 18 December 2017. Retrieved 16 December 2017.
    9. ↑ FDA Professional Drug Information on Zepatier.
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