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    Grazoprevir

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    2D Structure
    Also known as: 1350514-68-9, Mk-5172, Mk5172, Grazoprevir [inn], Mk-5172 anhydrous, Grazoprevir anhydrous
    Molecular Formula
    C38H50N6O9S
    Molecular Weight
    766.9  g/mol
    InChI Key
    OBMNJSNZOWALQB-NCQNOWPTSA-N
    FDA UNII
    8YE81R1X1J
    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. 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. The barrier for develoment of resistance to NS3/4A inhibitors is lower than that of NS5B inhibitors, another class of DAAs. 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 [DB11574]. 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 [DB11574] for genotypes 1a, 1b, and 4 of Hepatitis C. Grazoprevir and [DB11574] are used with or without [DB00811] 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. Grazoprevir is available as a fixed dose combination product with [DB11574] (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 [DB00811] depending on the the presence of resistance associated amino acid substitutions in the NS5A protein and previous treatment failure with [DB00811], [DB00008], [DB00022], or other NS3/4A inhibitors like [DB08873], [DB06290], or [DB05521]. When combined together, Grazoprevir and [DB11574] 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. It can be used in patients with compensated cirrhosis, human immunodeficiency virus co-infection, or severe kidney disease.
    Grazoprevir anhydrous is a Hepatitis C Virus NS3/4A Protease Inhibitor. The mechanism of action of grazoprevir anhydrous is as a HCV NS3/4A Protease Inhibitor, and Breast Cancer Resistance Protein Inhibitor, and Cytochrome P450 3A Inhibitor.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    (1R,18R,20R,24S,27S)-24-tert-butyl-N-[(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]-7-methoxy-22,25-dioxo-2,21-dioxa-4,11,23,26-tetrazapentacyclo[24.2.1.03,12.05,10.018,20]nonacosa-3,5(10),6,8,11-pentaene-27-carboxamide
    2.1.2 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
    2.1.3 InChI Key
    OBMNJSNZOWALQB-NCQNOWPTSA-N
    2.1.4 Canonical SMILES
    CC(C)(C)C1C(=O)N2CC(CC2C(=O)NC3(CC3C=C)C(=O)NS(=O)(=O)C4CC4)OC5=NC6=C(C=CC(=C6)OC)N=C5CCCCCC7CC7OC(=O)N1
    2.1.5 Isomeric SMILES
    CC(C)(C)[C@H]1C(=O)N2C[C@@H](C[C@H]2C(=O)N[C@@]3(C[C@H]3C=C)C(=O)NS(=O)(=O)C4CC4)OC5=NC6=C(C=CC(=C6)OC)N=C5CCCCC[C@@H]7C[C@H]7OC(=O)N1
    2.2 Other Identifiers
    2.2.1 UNII
    8YE81R1X1J
    2.3 Synonyms
    2.3.1 MeSH Synonyms

    1. Cyclopropanecarboxamide, N-((((1r,2r)-2-(5-(3-hydroxy-6-methoxy-2-quinoxalinyl)pentyl)cyclopropyl)oxy)carbonyl)-3-methyl-l-valyl-(4r)-4-hydroxy-l-prolyl-1-amino-n-(cyclopropylsulfonyl)-2-ethenyl-, Cyclic (1->2)-ether, (1r,2s)-

    2. Cyclopropanecarboxamide, N-((((1r,2r)-2-(5-(3-hydroxy-6-methoxy-2-quinoxalinyl)pentyl)cyclopropyl)oxy)carbonyl)-3-methyl-l-valyl-(4r)-4-hydroxy-l-prolyl-1-amino-n-(cyclopropylsulfonyl)-2-ethenyl-, Cyclic (1->2)-ether, Hydrate (1 :1) (1r,2s)-

    3. Grazoprevir Anhydrous

    4. Grazoprevir Hydrate

    5. Grazoprevir Monohydrate

    6. Mk 5172

    7. Mk-5172

    8. Mk-5172 Monohydrate

    9. Mk5172

    2.3.2 Depositor-Supplied Synonyms

    1. 1350514-68-9

    2. Mk-5172

    3. Mk5172

    4. Grazoprevir [inn]

    5. Mk-5172 Anhydrous

    6. Grazoprevir Anhydrous

    7. Mk 5172

    8. Grazoprevir Monohydrate

    9. Mk-5172 Monohydrate

    10. 8ye81r1x1j

    11. (1r,18r,20r,24s,27s)-24-tert-butyl-n-[(1r,2s)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]-7-methoxy-22,25-dioxo-2,21-dioxa-4,11,23,26-tetrazapentacyclo[24.2.1.03,12.05,10.018,20]nonacosa-3,5(10),6,8,11-pentaene-27-carboxamide

    12. Unii-8ye81r1x1j

    13. Grazoprevir [mi]

    14. Mk-5172; Grazoprevir

    15. Grazoprevir [who-dd]

    16. Schembl2175313

    17. Chembl2063090

    18. Gtpl11573

    19. Dtxsid50159234

    20. Chebi:132975

    21. Ex-a2253

    22. Bdbm50485492

    23. S3728

    24. Zinc95551509

    25. Akos030253227

    26. Ccg-270451

    27. Cs-1374

    28. Db11575

    29. Grazoprevir Component Of Zepatier

    30. Ino[11,12-b]quinoxaline-8-carboxamide

    31. Zepatier Component Of Grazoprevir

    32. Analog 15 [pmid: 24900473]

    33. Ncgc00378916-02

    34. Ac-29227

    35. As-55861

    36. Hy-15298

    37. D82934

    38. A887766

    39. Zepatier [elbasvir (ns5a Inhibitor) + Grazoprevir]

    40. Q19786991

    41. (1ar,5s,8s,10r,22ar)-5-tert-butyl-n-((1r,2s)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-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

    42. (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

    43. (1ar,5s,8s,10r,22ar)-5-tert-butyl-n-{(1r,2s)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-14-methoxy-3,6-di

    44. (1r,18r,20r,24s,27s)-24-tert-butyl-n-[(1r,2s)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl]-7-methoxy-22,25-dioxo-2,21-dioxa-4,11,23,26-tetraazapentacyclo[24.2.1.0?,??.0?,??.0??,??]nonacosa-3,5,7,9,11-pentaene-27-carboxamide

    45. (1r,2s)-n-[[[(1r,2r)-2-[5-(3-hydroxy-6-methoxy-2-quinoxalinyl)pentyl]cyclopropyl]oxy]carbonyl]-3-methyl-l-valyl-(4r)-4-hydroxy-l-prolyl-1-amino-n-(cyclopropylsulfonyl)-2-ethenyl-cyclopropanecarboxamide, Cyclic (1-->2)-ether;mk-5172

    46. (33r,35s,91r,92r,5s)-5-(tert-butyl)-n-((1r,2s)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalina-3(3,1)-pyrrolidina-9(1,2)-cyclopropanacyclotetradecaphane-35-carboxamide

    47. 1356446-42-8

    48. Cyclopropanecarboxamide, N-((((1r,2r)-2-(5-(3-hydroxy-6-methoxy-2-quinoxalinyl)pentyl)cyclopropyl)oxy)carbonyl)-3-methyl-l-valyl-(4r)-4-hydroxy-l-prolyl-1-amino-n-(cyclopropylsulfonyl)-2-ethenyl-, Cyclic (1->2)-ether, (1r,2s)-

    49. Oxo-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]dioxadiazacyclononadec

    2.4 Create Date
    2010-02-08
    3 Chemical and Physical Properties
    Molecular Weight 766.9 g/mol
    Molecular Formula C38H50N6O9S
    XLogP34.7
    Hydrogen Bond Donor Count3
    Hydrogen Bond Acceptor Count11
    Rotatable Bond Count8
    Exact Mass766.33599837 g/mol
    Monoisotopic Mass766.33599837 g/mol
    Topological Polar Surface Area204 Ų
    Heavy Atom Count54
    Formal Charge0
    Complexity1580
    Isotope Atom Count0
    Defined Atom Stereocenter Count7
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    4 Drug and Medication Information
    4.1 Drug Indication

    Grazoprevir is indicated in combination with [DB11574] (as the fixed dose combination product Zepatier) with or without [DB00811] for treatment of chronic HCV genotypes 1a, 1b, or 4 infection in adults.

    FDA Label

    Treatment of chronic hepatitis C

    5 Pharmacology and Biochemistry
    5.1 Pharmacology

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

    5.2 MeSH Pharmacological Classification

    Antiviral Agents

    Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)

    5.3 FDA Pharmacological Classification
    5.3.1 Active Moiety
    GRAZOPREVIR ANHYDROUS
    5.3.2 FDA UNII
    8YE81R1X1J
    5.3.3 Pharmacological Classes
    Mechanisms of Action [MoA] - Cytochrome P450 3A Inhibitors
    5.4 ATC Code

    J - Antiinfectives for systemic use

    J05 - Antivirals for systemic use

    J05A - Direct acting antivirals

    J05AP - Antivirals for treatment of hcv infections

    J05AP11 - Grazoprevir

    5.5 Absorption, Distribution and Excretion

    Absorption

    Grazoprevir reaches peak plasma concentration 0.5-3 hours after administration. 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.

    Route of Elimination

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

    Volume of Distribution

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

    Clearance

    The clearance of Grazoprevir has not been determined.

    5.6 Metabolism/Metabolites

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

    5.7 Biological Half-Life

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

    5.8 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). Grazoprevir inhibits the NS3/4protease enzymes of HCV genotype 1a, 1B, and 4 with IC50 values of 7pM, 4pM, and 62pM, respectively.