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CAS 698387-09-6

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Also known as: 698387-09-6, Hki-272, Neratinib (hki-272), Nerlynx, Hki 272, Pb-272

Molecular Formula

C₃₀H₂₉ClN₆O₃

Molecular Weight

557.0 g/mol

InChI Key

JWNPDZNEKVCWMY-VQHVLOKHSA-N

FDA UNII

JJH94R3PWB

Neratinib is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity. Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP-binding pocket of the receptor. Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation. Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells.

Neratinib is a Kinase Inhibitor. The mechanism of action of neratinib is as a Kinase Inhibitor, and P-Glycoprotein Inhibitor.

1 2D Structure

CAS 698387-09-6

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide

2.1.2 InChI

InChI=1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+

2.1.3 InChI Key

JWNPDZNEKVCWMY-VQHVLOKHSA-N

2.1.4 Canonical SMILES

CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)OCC4=CC=CC=N4)Cl)C#N)NC(=O)C=CCN(C)C

2.1.5 Isomeric SMILES

CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)OCC4=CC=CC=N4)Cl)C#N)NC(=O)/C=C/CN(C)C

2.2 Other Identifiers

2.2.1 UNII

JJH94R3PWB

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Hki 272

2. Hki-272

3. Hki272

4. N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide

5. Neratinib Maleate

6. Nerlynx

2.3.2 Depositor-Supplied Synonyms

1. 698387-09-6

2. Hki-272

3. Neratinib (hki-272)

4. Nerlynx

5. Hki 272

6. Pb-272

7. Jjh94r3pwb

8. Chembl180022

9. (2e)-n-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide

10. Cdp-820

11. 698387-09-6 (free Base)

12. Hki272

13. Way-179272

14. (2e)-n-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

15. (2e)-n-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

16. (e)-n-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

17. N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide

18. 2-butenamide, N-(4-((3-chloro-4-(2-pyridinylmethoxy)phenyl)amino)-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-, (2e)-

19. Neratinib [usan]

20. Neratinib(hki-272)

21. (e)-n-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

22. Neratinib [usan:inn]

23. Unii-jjh94r3pwb

24. Neratinib- Bio-x

25. (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide

26. Pb 272

27. Neratinib [inn]

28. Neratinib [mi]

29. Neratinib (usan/inn)

30. Neratinib - Hki-272

31. Neratinib [mart.]

32. Neratinib [who-dd]

33. Schembl571762

34. Schembl571763

35. Gtpl5686

36. Chebi:61397

37. Amy9255

38. Dtxsid70220132

39. Ex-a062

40. Bcpp000151

41. Zinc3916214

42. Bdbm50161957

43. Mfcd09752958

44. Nsc757439

45. Nsc800803

46. S2150

47. Way-179272-b

48. Akos005146340

49. Akos025149637

50. Bcp9000984

51. Ccg-270036

52. Db11828

53. Nsc-757439

54. Nsc-800803

55. Ncgc00241101-01

56. Ncgc00241101-03

57. Ncgc00241101-09

58. Ac-25073

59. As-16279

60. Bn164645

61. Hy-32721

62. N1062

63. Ec-000.2260

64. A25338

65. D08950

66. 387n096

67. Q-101402

68. Q6995920

69. Brd-k85606544-001-01-8

70. (2e)-n-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide Neratinib

71. (2e)-n-[4-[[3-chloro-4-(2-pyridinylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide

72. (e)-4-dimethylamino-but-2-enoic Acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-3-cyano-7-ethoxy-quinolin-6-yl}-amide

73. 4-dimethylamino-but-2-enoic Acid {4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-3-cyano-7-ethoxy-quinolin-6-yl}-amide

74. Hki-272; Pb272;;(2e)-n-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide;hki-272

75. N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

76. N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)butanamide

2.4 Create Date

2006-10-25

3 Chemical and Physical Properties

Molecular Formula	C₃₀H₂₉ClN₆O₃
Molecular Weight	557.0 g/mol
XLogP3	4.9
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	11
Exact Mass	556.1989665 g/mol
Monoisotopic Mass	556.1989665 g/mol
Topological Polar Surface Area	112 Å²
Heavy Atom Count	40
Formal Charge	0
Complexity	881
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	1
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Information

1 of 1
Drug Name	NERLYNX
Active Ingredient	NERATINIB MALEATE
Company	PUMA BIOTECH (Application Number: N208051. Patents: 6288082, 7399865, 7982043, 8518446, 8790708, 9139558, 9211291, 9630946)

4.2 Drug Indication

For use as an extended adjuvant treatment in adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

FDA Label

Nerlynx is indicated for the extended adjuvant treatment of adult patients with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Neratinib is a tyrosine kinase inhibitor which exhibits antitumor action against Epidermal Growth Factor Receptor (EGFR), HER2, and Human Epidermal Growth Factor Receptor 4 (HER4) postive carcinomas.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

NERATINIB

5.2.2 FDA UNII

JJH94R3PWB

5.2.3 Pharmacological Classes

Kinase Inhibitors [MoA]; P-Glycoprotein Inhibitors [MoA]; Kinase Inhibitor [EPC]

5.3 ATC Code

L01EH02

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EH - Human epidermal growth factor receptor 2 (her2) tyrosine kinase inhibitors

L01EH02 - Neratinib

5.4 Absorption, Distribution and Excretion

Absorption

Neratinib and its major active metabolites M3. M6, and M7 have a Tmax of 2-8 h. Administration with a high fat meal increases Cmax by 1.7-fold and total exposure by 2.2-fold. Administration with a standard meal increases Cmax by 1.2-fold and total exposure by 1.1-fold. Administration with gastric acid reducing agents such as proton pump inhibitors reduces Cmax by 71% and total exposure by 65%.

Route of Elimination

97.1% of the total dose is excreted in the feces and 1.13% in the urine.

Volume of Distribution

The apparent volume of distribution at steady state is 6433 L.

Clearance

The total clearance during multiple doses is 216 L/h for after the first dose and 281 L/h during steady state.

5.5 Metabolism/Metabolites

Neratinib is mainly undergoes metabolism via CYP3A4. It is also metabolized by flavin-containing monooxygenase to a lesser extent. The systemic exposures of neratinib's active metabolites M3, M6, M7, and M11 are 15%, 33%, 22%, and 4%.

5.6 Biological Half-Life

The mean half life of elimination ranges from 7-17 h following a single dose. The mean plasma half life during multiple doses is 14.6 h for neratinib, 21.6 h for M3, 13.8 h for M6, and 10.4 h for M7.

5.7 Mechanism of Action

Neratinib binds to and irreversibly inhibits EGFR, HER2, and HER4. This prevents auotphoshorylation of tyrosine residues on the receptor and reduces oncogenic signalling through the mitogen-activated protein kinase and Akt pathways.

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