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    Avapritinib

    ACTIVE PHARMA INGREDIENTS

    DEVELOPMENTS

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    2D Structure
    Also known as: Blu-285, 1703793-34-3, Ayvakit, Avapritinib [inn], Blu285, (1s)-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine
    Molecular Formula
    C26H27FN10
    Molecular Weight
    498.6  g/mol
    InChI Key
    DWYRIWUZIJHQKQ-SANMLTNESA-N
    FDA UNII
    513P80B4YJ
    Avapritinib is an orally bioavailable inhibitor of specific mutated forms of platelet-derived growth factor receptor alpha (PDGFR alpha; PDGFRa) and mast/stem cell factor receptor c-Kit (SCFR), with potential antineoplastic activity. Upon oral administration, avapritinib specifically binds to and inhibits specific mutant forms of PDGFRa and c-Kit, including the PDGFRa D842V mutant and various KIT exon 17 mutants. This results in the inhibition of PDGFRa- and c-Kit-mediated signal transduction pathways and the inhibition of proliferation in tumor cells that express these PDGFRa and c-Kit mutants. PDGFRa and c-Kit, protein tyrosine kinases and tumor-associated antigens (TAAs), are mutated in various tumor cell types; they play key roles in the regulation of cellular proliferation.
    Avapritinib is a Kinase Inhibitor. The mechanism of action of avapritinib is as a Tyrosine Kinase Inhibitor, and Cytochrome P450 2C9 Inhibitor, and P-Glycoprotein Inhibitor, and Breast Cancer Resistance Protein Inhibitor, and Multidrug and Toxin Extrusion Transporter 1 Inhibitor, and Multidrug and Toxin Extrusion Transporter 2 K Inhibitor, and Bile Salt Export Pump Inhibitor.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    (1S)-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine
    2.1.2 InChI
    InChI=1S/C26H27FN10/c1-26(28,20-3-5-22(27)6-4-20)21-13-29-25(30-14-21)36-9-7-35(8-10-36)24-23-11-18(16-37(23)33-17-31-24)19-12-32-34(2)15-19/h3-6,11-17H,7-10,28H2,1-2H3/t26-/m0/s1
    2.1.3 InChI Key
    DWYRIWUZIJHQKQ-SANMLTNESA-N
    2.1.4 Canonical SMILES
    CC(C1=CC=C(C=C1)F)(C2=CN=C(N=C2)N3CCN(CC3)C4=NC=NN5C4=CC(=C5)C6=CN(N=C6)C)N
    2.1.5 Isomeric SMILES
    C[C@](C1=CC=C(C=C1)F)(C2=CN=C(N=C2)N3CCN(CC3)C4=NC=NN5C4=CC(=C5)C6=CN(N=C6)C)N
    2.2 Other Identifiers
    2.2.1 UNII
    513P80B4YJ
    2.3 Synonyms
    2.3.1 MeSH Synonyms

    1. (1s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-yl)-1-piperazinyl)-5-pyrimidinyl)ethanamine

    2. 5-pyrimidinemethanamine, Alpha-(4-fluorophenyl)-alpha-methyl-2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-yl)-1-piperazinyl)-, (alphas)-

    3. Ayvakit

    4. Blu-285

    2.3.2 Depositor-Supplied Synonyms

    1. Blu-285

    2. 1703793-34-3

    3. Ayvakit

    4. Avapritinib [inn]

    5. Blu285

    6. (1s)-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine

    7. 513p80b4yj

    8. C-366

    9. 70c366

    10. X720776

    11. X-720776

    12. Ayvakyt

    13. Mfcd31544325

    14. Ayvakit (tn)

    15. Avapritinib [mi]

    16. Avapritinib (usan/inn)

    17. Avapritinib [usan]

    18. Avapritinib (blu-285)

    19. Blu-285 (avapritinib)

    20. Avapritinib [who-dd]

    21. Unii-513p80b4yj

    22. Chembl4204794

    23. Schembl16652297

    24. Gtpl10368

    25. Avapritinib [orange Book]

    26. Blu 285

    27. Bdbm469269

    28. Dtxsid301027935

    29. Amy16753

    30. Ex-a1366

    31. Us10807985, Compound 44

    32. Nsc801082

    33. S8553

    34. Akos037648993

    35. Ccg-269677

    36. Cs-7577

    37. Db15233

    38. Nsc-801082

    39. (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine

    40. Ac-31598

    41. Bb166456

    42. Bs-16206

    43. Hy-101561

    44. D11279

    45. Q29213676

    46. (1s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-yl)-1-piperazinyl)-5-pyrimidinyl)ethanamine

    47. (1s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine

    48. (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-yl)piperazin-yl)pyrimidin-5-yl)ethan-1-amine

    49. (s)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine

    50. 5-pyrimidinemethanamine, .alpha.-(4-fluorophenyl)-.alpha.-methyl-2-(4-(6-(1-methyl-1h-pyrazol-4-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-yl)-1-piperazinyl)-, (.alpha.s)-

    2.4 Create Date
    2016-02-23
    3 Chemical and Physical Properties
    Molecular Weight 498.6 g/mol
    Molecular Formula C26H27FN10
    XLogP31.9
    Hydrogen Bond Donor Count1
    Hydrogen Bond Acceptor Count9
    Rotatable Bond Count5
    Exact Mass498.24041907 g/mol
    Monoisotopic Mass498.24041907 g/mol
    Topological Polar Surface Area106 Ų
    Heavy Atom Count37
    Formal Charge0
    Complexity752
    Isotope Atom Count0
    Defined Atom Stereocenter Count1
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    4 Drug and Medication Information
    4.1 Drug Indication

    Avapritinib is indicated for the treatment of unresectable, metastatic gastrointestinal stromal tumors with a platelet-derived growth factor receptor alpha exon 18 mutation.

    Treatment of mastocytosis

    Treatment of all conditions included in the category of malignant neoplasms (except haematopoietic and lymphoid tissue neoplasms)

    Ayvakyt is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) harbouring the platelet-derived growth factor receptor alpha (PDGFRA) D842V mutation.

    5 Pharmacology and Biochemistry
    5.1 Pharmacology

    Avapritinib is a selective kinase inhibitor that negatively modulates the action of cell transporters to resensitize them to other chemotherapies. It has a long duration of action as it is given once daily. Patients should be counselled regarding the risk of intracranial hemorrhage, CNS effects, and embryo-fetal toxicity.

    5.2 FDA Pharmacological Classification
    5.2.1 Active Moiety
    AVAPRITINIB
    5.2.2 FDA UNII
    513P80B4YJ
    5.2.3 Pharmacological Classes
    Breast Cancer Resistance Protein Inhibitors [MoA]; Cytochrome P450 2C9 Inhibitors [MoA]; Kinase Inhibitor [EPC]; Multidrug and Toxin Extrusion Transporter 1 Inhibitors [MoA]; Multidrug and Toxin Extrusion Transporter 2 K Inhibitors [MoA]; P-Glycoprotein Inhibitors [MoA]; Tyrosine Kinase Inhibitors [MoA]; Bile Salt Export Pump Inhibitors [MoA]
    5.3 ATC Code

    L01EX18

    L - Antineoplastic and immunomodulating agents

    L01 - Antineoplastic agents

    L01E - Protein kinase inhibitors

    L01EX - Other protein kinase inhibitors

    L01EX18 - Avapritinib

    5.4 Absorption, Distribution and Excretion

    Absorption

    A 300mg oral dose of avapritinib reaches a Cmax of 813ng/mL with a Tmax of 2.0-4.1h and an AUC of 15400h\*ng/mL.

    Route of Elimination

    Avapritinib is 70% eliminated in the feces with 11% as the unchanged drug and 18% eliminated in the urine with 0.23% as the unchanged drug.

    Volume of Distribution

    The mean apparent volume of distribution is 1200L.

    Clearance

    The mean apparent oral clearance of avapritinib is 19.5L/h.

    5.5 Metabolism/Metabolites

    Avapritinib is metabolized mainly by CYP3A4 and CYP2C9 in vitro. A 310mg oral dose is recovered as 49% unchanged drug, 35% hydroxy glucuronide metabolite, and 14% oxidatively deaminated metabolite.

    5.6 Biological Half-Life

    The half life of avapritinib is 32-57h.

    5.7 Mechanism of Action

    Avapritinib has a negative modulating effect on the transporters ABCB1 and ABCG2, which mediate the multidrug resistance phenotype of some cancers. This modulation may be due to interactions of avapritinib with the drug binding pocket of these transporters. Negative modulation of these transporters, resensitizes cancerous cells to treatment with chemotherapeutic agents like [paclitaxel].