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    CAS 698387-09-6

    BUILDING BLOCK

    MARKET PLACE

    PharmaCompass
    Xls

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    2D Structure
    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

    2D Structure

    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 Weight 557.0 g/mol
    Molecular Formula C30H29ClN6O3
    XLogP34.9
    Hydrogen Bond Donor Count2
    Hydrogen Bond Acceptor Count8
    Rotatable Bond Count11
    Exact Mass556.1989665 g/mol
    Monoisotopic Mass556.1989665 g/mol
    Topological Polar Surface Area112 Ų
    Heavy Atom Count40
    Formal Charge0
    Complexity881
    Isotope Atom Count0
    Defined Atom Stereocenter Count0
    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 NameNERLYNX
    Active IngredientNERATINIB MALEATE
    CompanyPUMA 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.