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CAS 1365970-03-1
Also known as: Abt-493, Glecaprevir [usan], 1365970-03-1, A-1282576.0, K6buu8j72p, A-1282576
Molecular Formula
C38H46F4N6O9S
Molecular Weight
838.9  g/mol
InChI Key
MLSQGNCUYAMAHD-ITNVBOSISA-N
FDA UNII
K6BUU8J72P

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 [DB13878], 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. 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. Glecaprevir is available as an oral combination therapy with [DB13878] 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. 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. 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.
Glecaprevir is a Hepatitis C Virus NS3/4A Protease Inhibitor. The mechanism of action of glecaprevir is as a HCV NS3/4A Protease Inhibitor, and P-Glycoprotein Inhibitor, and Breast Cancer Resistance Protein Inhibitor, and Organic Anion Transporting Polypeptide 1B1 Inhibitor, and Organic Anion Transporting Polypeptide 1B3 Inhibitor, and Cytochrome P450 3A Inhibitor, and Cytochrome P450 1A2 Inhibitor, and UGT1A1 Inhibitor.
1 2D Structure

CAS 1365970-03-1

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(1R,14E,18R,22R,26S,29S)-26-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropyl)sulfonylcarbamoyl]cyclopropyl]-13,13-difluoro-24,27-dioxo-2,17,23-trioxa-4,11,25,28-tetrazapentacyclo[26.2.1.03,12.05,10.018,22]hentriaconta-3,5,7,9,11,14-hexaene-29-carboxamide
2.1.2 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
2.1.3 InChI Key
MLSQGNCUYAMAHD-ITNVBOSISA-N
2.1.4 Canonical SMILES
CC1(CC1)S(=O)(=O)NC(=O)C2(CC2C(F)F)NC(=O)C3CC4CN3C(=O)C(NC(=O)OC5CCCC5OCC=CC(C6=NC7=CC=CC=C7N=C6O4)(F)F)C(C)(C)C
2.1.5 Isomeric SMILES
CC1(CC1)S(=O)(=O)NC(=O)[C@]2(C[C@H]2C(F)F)NC(=O)[C@@H]3C[C@@H]4CN3C(=O)[C@@H](NC(=O)O[C@@H]5CCC[C@H]5OC/C=C/C(C6=NC7=CC=CC=C7N=C6O4)(F)F)C(C)(C)C
2.2 Other Identifiers
2.2.1 UNII
K6BUU8J72P
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Abt-493

2.3.2 Depositor-Supplied Synonyms

1. Abt-493

2. Glecaprevir [usan]

3. 1365970-03-1

4. A-1282576.0

5. K6buu8j72p

6. A-1282576

7. A-12825760

8. 1365970-03-1 (free)

9. Abt 493

10. (3ar,7s,10s,12r,21e,24ar)-7-tert-butyl-n-[(1r,2r)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)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

11. (3ar,7s,10s,12r,21e,24ar)-7-tert-butyl-n-{(1r,2r)-2(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl}-20,20-difluoro5,8-dioxo-2,3,3a,5,6,7,8,11,12,20,23,24a-dodecahydro-1h,10h-9,12methanocyclopenta[18,19][1,10,17,3,6]trioxadiazacyclononadecino[11,12-b]quinoxaline-10carboxamide

12. Unii-k6buu8j72p

13. Maviret

14. (3ar,7s,10s,12r,21e,24ar)-7-tert-butyl-n-[(1r,2r)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclop Ropyl]-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

15. O31

16. Glecaprevir [mi]

17. Abt-493(glecaprevir)

18. Glecaprevir [inn]

19. Glecaprevir (usan/inn)

20. Glecaprevir [who-dd]

21. Schembl883097

22. Abt493

23. Chembl3545363

24. Gtpl11267

25. Glecaprevir [orange Book]

26. Dtxsid901027945

27. (1r,14e,18r,22r,26s,29s)-26-tert-butyl-n-[(1r,2r)-2-(difluoromethyl)-1-[(1-methylcyclopropyl)sulfonylcarbamoyl]cyclopropyl]-13,13-difluoro-24,27-dioxo-2,17,23-trioxa-4,11,25,28-tetrazapentacyclo[26.2.1.03,12.05,10.018,22]hentriaconta-3,5,7,9,11,14-hexaene-29-carboxamide

28. Amy38157

29. Ex-a1940

30. Mavyret Component Glecaprevir

31. Bdbm50573891

32. S5720

33. Cs-8098

34. Db13879

35. Ac-33419

36. Hy-17634

37. J3.646.120i

38. D10814

39. 3,6]trioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide

40. (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

41. (3ar,7s,10s,12r,21e,24ar)-7-tert-butyl-n-[(1r,2r)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclop

42. (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

43. Cyclopropanecarboxamide, N-((((1r,2r)-2-((4,4-difluoro-4-(3-hydroxy-2-quinoxalinyl)-2-buten-1-yl)oxy)cyclopentyl)oxy)carbonyl)-3-methyl-l-valyl-(4r)-4-hydroxy-l-prolyl-1-amino-2-(difluoromethyl)-n-((1-methylcyclopropyl)sulfonyl)-, Cyclic (1->2)-ether, (1r,2r)-

44. Ropyl]-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,

2.4 Create Date
2012-11-30
3 Chemical and Physical Properties
Molecular Weight 838.9 g/mol
Molecular Formula C38H46F4N6O9S
XLogP34.6
Hydrogen Bond Donor Count3
Hydrogen Bond Acceptor Count15
Rotatable Bond Count7
Exact Mass838.29831089 g/mol
Monoisotopic Mass838.29831089 g/mol
Topological Polar Surface Area204 Ų
Heavy Atom Count58
Formal Charge0
Complexity1760
Isotope Atom Count0
Defined Atom Stereocenter Count7
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count1
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 1  
Drug NameMAVYRET
Active IngredientGLECAPREVIR; PIBRENTASVIR
CompanyABBVIE INC (Application Number: N209394. Patents: 8648037, 8937150, 9321807, 9586978)

4.2 Drug 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


Maviret is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults and children aged 3 years and older.

Maviret coated granules is indicated for the treatment of chronic hepatitis C virus (HCV) infection in children 3 years and older.


5 Pharmacology and Biochemistry
5.1 Pharmacology

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. In a QT study, glecaprevir is not shown to prolong the QTc interval.


5.2 FDA Pharmacological Classification
5.2.1 Active Moiety
GLECAPREVIR
5.2.2 FDA UNII
K6BUU8J72P
5.2.3 Pharmacological Classes
Mechanisms of Action [MoA] - UGT1A1 Inhibitors
5.3 ATC Code

J05AP57


5.4 Absorption, Distribution and Excretion

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%.


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.


5.5 Metabolism/Metabolites

Glecaprevir undergoes limited secondary metabolism in vitro, predominantly by CYP3A.


5.6 Biological Half-Life

The elimination half life (t1/2) is approximately 6 hours.


5.7 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. 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. NS4A is a cofactor for NS3 that directs the localization of NS3 and modulates its enzymatic activities. 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.


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