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Grazoprevir

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Grazoprevir

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Chemistry

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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

Grazoprevir

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 Formula	C₃₈H₅₀N₆O₉S
Molecular Weight	766.9 g/mol
XLogP3	4.7
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	8
Exact Mass	766.33599837 g/mol
Monoisotopic Mass	766.33599837 g/mol
Topological Polar Surface Area	204 Å²
Heavy Atom Count	54
Formal Charge	0
Complexity	1580
Isotope Atom Count	0
Defined Atom Stereocenter Count	7
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

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.

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