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1 Health Canada Patents

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Synopsis

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Chemistry

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Also known as: 630420-16-5, Bms-650032, Sunvepra, Bms 650032, Bms650032, S9x0krj00s

Molecular Formula

C₃₅H₄₆ClN₅O₉S

Molecular Weight

748.3 g/mol

InChI Key

XRWSZZJLZRKHHD-WVWIJVSJSA-N

FDA UNII

S9X0KRJ00S

Asunaprevir is an orally bioavailable inhibitor of the nonstructural protein 3 (NS3), with potential activity against hepatitis C virus (HCV). Upon administration, asunaprevir binds to the active center of the HCV NS3 and prevents NS3 protease-mediated polyprotein maturation. This disrupts the processing of viral proteins required for HCV replication. NS3, a serine protease, is essential for the proteolytic cleavages within the HCV polyprotein and plays a key role during HCV viral RNA replication. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family.

1 2D Structure

Asunaprevir

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

tert-butyl N-[(2S)-1-[(2S,4R)-4-(7-chloro-4-methoxyisoquinolin-1-yl)oxy-2-[[(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

2.1.2 InChI

InChI=1S/C35H46ClN5O9S/c1-9-19-16-35(19,31(44)40-51(46,47)22-11-12-22)39-28(42)25-15-21(49-29-24-14-20(36)10-13-23(24)26(48-8)17-37-29)18-41(25)30(43)27(33(2,3)4)38-32(45)50-34(5,6)7/h9-10,13-14,17,19,21-22,25,27H,1,11-12,15-16,18H2,2-8H3,(H,38,45)(H,39,42)(H,40,44)/t19-,21-,25+,27-,35-/m1/s1

2.1.3 InChI Key

XRWSZZJLZRKHHD-WVWIJVSJSA-N

2.1.4 Canonical SMILES

CC(C)(C)C(C(=O)N1CC(CC1C(=O)NC2(CC2C=C)C(=O)NS(=O)(=O)C3CC3)OC4=NC=C(C5=C4C=C(C=C5)Cl)OC)NC(=O)OC(C)(C)C

2.1.5 Isomeric SMILES

CC(C)(C)[C@@H](C(=O)N1C[C@@H](C[C@H]1C(=O)N[C@@]2(C[C@H]2C=C)C(=O)NS(=O)(=O)C3CC3)OC4=NC=C(C5=C4C=C(C=C5)Cl)OC)NC(=O)OC(C)(C)C

2.2 Other Identifiers

2.2.1 UNII

S9X0KRJ00S

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Bms 650032

2. Bms-650032

2.3.2 Depositor-Supplied Synonyms

1. 630420-16-5

2. Bms-650032

3. Sunvepra

4. Bms 650032

5. Bms650032

6. S9x0krj00s

7. 1,1-dimethylethyl ((1s)-1-{((2s,4r)-4-(7-chloro-4-methoxyisoquinolin-1-yloxy)-2-({(1r,2s)-1-((cyclopropylsulfonyl)carbamoyl)-2-ethenylcyclopropyl}carbamoyl) Pyrrolidin-1-yl)carbonyl}-2,2-dimethylpropyl)carbamate

8. Tert-butyl N-[(2s)-1-[(2s,4r)-4-(7-chloro-4-methoxyisoquinolin-1-yl)oxy-2-[[(1r,2s)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate

9. Asunaprevir (bms-650032)

10. Cyclopropanecarboxamide, N-((1,1-dimethylethoxy)carbonyl)-3-methyl-l-valyl-(4r)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-l-prolyl-1-amino-n-(cyclopropylsulfonyl)-2-ethenyl-, (1r,2s)-

11. N-(tert-butoxycarbonyl)-3-methyl-l-valyl-(4r)-4-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-n-{(1r,2s)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-l-prolinamide

12. Tert-butyl ((s)-1-((2s,4r)-4-((7-chloro-4-methoxyisoquinolin-1-yl)oxy)-2-(((1r,2s)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

13. Asunaprevir [usan]

14. Asunaprevir (jan/usan)

15. Asunaprevir [usan:inn]

16. Unii-s9x0krj00s

17. Sunvepratrade

18. Sunvepra (tn)

19. 2r9

20. Tert-butyl N-[(1s)-1-[(2s,4r)-4-[(7-chloro-4-methoxy-1-isoquinolyl)oxy]-2-[[(1r,2s)-1-(cyclopropylsulfonylcarbamoyl)-2-vinyl-cyclopropyl]carbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamate

21. Asunaprevir [mi]

22. Asunaprevir [inn]

23. Asunaprevir [jan]

24. Asunaprevir [who-dd]

25. Asunaprevir; Bms-650032

26. Schembl2630655

27. Chembl2105735

28. Gtpl10882

29. Ex-a386

30. Chebi:134723

31. Dtxsid201026065

32. (1r,2s)-n-[(1,1-dimethylethoxy)carbonyl]-3-methyl-l-valyl-(4r)-4-[(7-chloro-4-methoxy-1-isoquinolinyl)oxy]-l-prolyl-1-amino-n-(cyclopropylsulfonyl)-2-ethenylcyclopropanecarboxamide

33. Amy38775

34. Bcp08230

35. Bdbm50287594

36. Mfcd27987900

37. Zinc85540202

38. Akos037515831

39. Cs-0674

40. Db11586

41. Compound 24 [pmid: 24564672]

42. Ncgc00378691-02

43. Ncgc00378691-05

44. Hy-14434

45. Asunaprevir;bms650032;bms-650032

46. D10093

47. A857563

48. Q4811881

49. 1,1-dimethylethyl ((1s)-1-(((2s,4r)-4-(7-chloro-4methoxyisoquinolin-1-yloxy)-2- (((1r,2s)-1-((cyclopropylsulfonyl)carbamoyl)-2-ethenylcyclopropyl)carbamoyl) Pyrrolidin-1-yl)carbonyl)-2,2-dimethylpropyl)carbamate

50. Bms650032;(1r,2s)-n-[(1,1-dimethylethoxy)carbonyl]-3-methyl-l-valyl-(4r)-4-[(7-chloro-4-methoxy-1-isoquinolinyl)oxy]-l-prolyl-1-amino-n-(cyclopropylsulfonyl)-2-ethenylcyclopropanecarboxamide

51. Carbamic Acid, [(1s)-1-[[(2s,4r)-4-[(7-chloro-4-methoxy-1-isoquinolinyl)oxy]-2-[[[(1r,2s)-1-[[(cyclopropylsulfonyl)amino]carbonyl]-2-ethenylcyclopropyl]amino]carbonyl]-1-pyrrolidinyl]carbonyl]-2,2-dimethylpropyl]-, 1,1-dimethylethyl Ester

52. Cyclopropanecarboxamide, N-((1,1-dimethylethoxy)carbonyl)-3-methyl-l-valyl-(4r)-4- ((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-l-prolyl-1-amino-n-(cyclopropylsulfonyl)-2- Ethenyl-, (1r,2s)-

53. Tert-butyl ((2s)-1-((2s,4r)-4-((7-chloro-4-methoxyisoquinolin-1-yl)oxy)-2-(((1r,2s)-1-((cyclopropanesulfonyl)carbamoyl)-2-ethenylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

2.4 Create Date

2007-06-11

3 Chemical and Physical Properties

Molecular Formula	C₃₅H₄₆ClN₅O₉S
Molecular Weight	748.3 g/mol
XLogP3	4.9
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	14
Exact Mass	747.2704769 g/mol
Monoisotopic Mass	747.2704769 g/mol
Topological Polar Surface Area	191 Å²
Heavy Atom Count	51
Formal Charge	0
Complexity	1470
Isotope Atom Count	0
Defined Atom Stereocenter Count	5
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

Asunaprevir is indicated in combination with other agents for the treatment of chronic hepatitis C in adult patients with hepatitis C virus genotypes 1 or 4 and compensated liver cirrhosis. Hepatitis C is a liver disease caused by the hepatitis C virus. The chronic state of this condition accounts for 60-80% of the cases from which the risk of cirrhosis of the liver within 20 years is of around 15-30%. The genotype 1 is the most common type of hepatitis C in the United States and the most difficult to treat.

Treatment of chronic hepatitis C

5 Pharmacology and Biochemistry

5.1 Pharmacology

Studies in vitro demonstrated a significant antiviral activity in HCV replicon cell systems with an EC50 of 4nm and 1nm against the HCV genotype 1a and 1b respectively. These studies showed a limited activity against the genotypes 2 and 3. This property makes asunaprevir a highly selective anti-HCV agent that is not effective against HCV closely related virus. Asunaprevir produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection.In clinical studies, it has been shown that asunaprevir is well-tolerated and the mean maximum HCV RNA level reduction from baseline was of approximately 2.87 log10 IU/ml. Monotherapy clinical studies with asunaprevir showed a mean maximum decline of HCV RNA in the range of 0.28-2.87 log10 IU/ml when administered in increasing doses from 10-600 mg. When asunaprevir was used as a combination product, it was possible to obtain a sustained virological response (aviremia 24 weeks after completion of therapy) in 83-92% of the patients.

5.2 MeSH Pharmacological Classification

Protease Inhibitors

Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES). (See all compounds classified as Protease Inhibitors.)

5.3 ATC Code

J - Antiinfectives for systemic use

J05 - Antivirals for systemic use

J05A - Direct acting antivirals

J05AP - Antivirals for treatment of hcv infections

J05AP06 - Asunaprevir

5.4 Absorption, Distribution and Excretion

Absorption

In preclinical studies, asunaprevir showed a high liver-to-plasma AUC ratio. It is rapidly absorbed within 30 minutes of administration. Clinical pharmacokinetic studies showed a T_max of 2-4 hours. The pharmacokinetic profile act in a dose-proportional manner and in a dose of 100 mg the steady-state C_max and AUC was 572 ng/ml and 1887 ng x h/mL. The absolute bioavailability is reported to be 9.3%. The absorption of asunaprevir is increased with food.

Route of Elimination

Asunaprevir is primarily eliminated via the feces. From the administered dose, 84% is excreted by feces mainly as metabolites and less than 1% of the dose is recovered as metabolites in the urine. The proportion of unchanged asunaprevir recovered in feces represents only 7.5% of the dose.

Volume of Distribution

The registered volume of distribution at steady state is 194 L.

Clearance

Clinical pharmacokinetic studies showed a mean oral clearance of 302-491 L/h.

5.5 Metabolism/Metabolites

Asunaprevir is metabolized by the liver. The metabolism is mainly marked by oxidative reactions mediated by the activity of CYP3A. Asunaprevir seems to weakly induce its own metabolism and from the circulating dose, just about 5% of the administered dose is formed by metabolites. The metabolites of asunaprevir are formed after mono- and bis-oxidation, N-dealkylation, loss of isoquinoline ring and O-demethylation. All the metabolic reactions form about 15 metabolites and studies have reported that the main metabolic activity is performed by CYP3A4 and CYP3A5 with some minor activity from CYP2A6, CYP2B6, CYP2C9, CYP2C19 and CYP2D6.

5.6 Biological Half-Life

Clinical pharmacokinetic studies showed a mean terminal half-life of 15-20 hours.

5.7 Mechanism of Action

Asunaprevir is a highly active HCV NS3 protease inhibitor. The genome of HCV has a positive polarity which allows it to be translated into a protein in the host cell without further transformation steps. However, the resultant protein needs to be divided by the enzyme NS3 protease into single proteins in order to be able to exert its enzymatic activity or structural role. Therefore, due to NS3 vital importance for viral replication, the inhibiting action of asunaprevir causes a robust antiviral activity.

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