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    Ripretinib

    ACTIVE PHARMA INGREDIENTS

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    2D Structure
    Also known as: 1442472-39-0, Dcc-2618, N-{4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3- yl]-2-fluorophenyl}-n'-phenylurea, Urea, n-[4-bromo-5-[1-ethyl-1,2-dihydro-7-(methylamino)-2-oxo-1,6- naphthyridin-3-yl]-2-fluorophenyl]-n'-phenyl-39-0, Ripretinib free base, Ripretinib [usan]
    Molecular Formula
    C24H21BrFN5O2
    Molecular Weight
    510.4  g/mol
    InChI Key
    CEFJVGZHQAGLHS-UHFFFAOYSA-N
    FDA UNII
    9XW757O13D
    Ripretinib is an orally bioavailable switch pocket control inhibitor of wild-type and mutated forms of the tumor-associated antigens (TAA) mast/stem cell factor receptor (SCFR) KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha; PDGFRa), with potential antineoplastic activity. Upon oral administration, ripretinib targets and binds to both wild-type and mutant forms of KIT and PDGFRa specifically at their switch pocket binding sites, thereby preventing the switch from inactive to active conformations of these kinases and inactivating their wild-type and mutant forms. This abrogates KIT/PDGFRa-mediated tumor cell signaling and prevents proliferation in KIT/PDGFRa-driven cancers. DCC-2618 also inhibits several other kinases, including vascular endothelial growth factor receptor type 2 (VEGFR2; KDR), angiopoietin-1 receptor (TIE2; TEK), PDGFR-beta and macrophage colony-stimulating factor 1 receptor (FMS; CSF1R), thereby further inhibiting tumor cell growth. KIT and PDGFRa are tyrosine kinase receptors that are upregulated or mutated in a variety of cancer cell types; mutated forms play a key role in the regulation of tumor cell proliferation and resistance to chemotherapy.
    Ripretinib is a Kinase Inhibitor. The mechanism of action of ripretinib is as a Stem Cell Factor (KIT) Receptor Inhibitor, and Platelet-derived Growth Factor alpha Receptor Inhibitor, and Cytochrome P450 2C8 Inhibitor, and P-Glycoprotein Inhibitor, and Breast Cancer Resistance Protein Inhibitor.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea
    2.1.2 InChI
    InChI=1S/C24H21BrFN5O2/c1-3-31-21-12-22(27-2)28-13-14(21)9-17(23(31)32)16-10-20(19(26)11-18(16)25)30-24(33)29-15-7-5-4-6-8-15/h4-13H,3H2,1-2H3,(H,27,28)(H2,29,30,33)
    2.1.3 InChI Key
    CEFJVGZHQAGLHS-UHFFFAOYSA-N
    2.1.4 Canonical SMILES
    CCN1C2=CC(=NC=C2C=C(C1=O)C3=CC(=C(C=C3Br)F)NC(=O)NC4=CC=CC=C4)NC
    2.2 Other Identifiers
    2.2.1 UNII
    9XW757O13D
    2.3 Synonyms
    2.3.1 MeSH Synonyms

    1. 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea

    2. Urea, N-(4-bromo-5-(1-ethyl-1,2-dihydro-7-(methylamino)-2-oxo-1,6-naphthyridin-3-yl)-2-fluorophenyl)-n'-phenyl-

    2.3.2 Depositor-Supplied Synonyms

    1. 1442472-39-0

    2. Dcc-2618

    3. N-{4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3- Yl]-2-fluorophenyl}-n'-phenylurea

    4. Urea, N-[4-bromo-5-[1-ethyl-1,2-dihydro-7-(methylamino)-2-oxo-1,6- Naphthyridin-3-yl]-2-fluorophenyl]-n'-phenyl-39-0

    5. Ripretinib Free Base

    6. Ripretinib [usan]

    7. Ripretinib (dcc-2618)

    8. 9xw757o13d

    9. Ripretinib (usan)

    10. 1442472-39-0 (free Base)

    11. 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea

    12. Qinlock

    13. 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea

    14. N-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-n'-phenylurea

    15. Urea, N-(4-bromo-5-(1-ethyl-1,2-dihydro-7-(methylamino)-2-oxo-1,6-naphthyridin-3-yl)-2-fluorophenyl)-n'-phenyl-

    16. Quinlock

    17. Qinlock (tn)

    18. Ripretinib [mi]

    19. Ripretinib [inn]

    20. Ripretinib [who-dd]

    21. Unii-9xw757o13d

    22. Gtpl9175

    23. Chembl4216467

    24. Ripretinib [orange Book]

    25. Schembl14999718

    26. Dcc2618

    27. Dtxsid201027956

    28. Bcp29218

    29. Ex-a4883

    30. S8757

    31. At18473

    32. Db14840

    33. Ac-36722

    34. Hy-112306

    35. Cs-0044835

    36. D11353

    37. Dcc 2618;dcc2618;kit/pdgfr Inhibitor;ripretinib

    2.4 Create Date
    2013-07-08
    3 Chemical and Physical Properties
    Molecular Weight 510.4 g/mol
    Molecular Formula C24H21BrFN5O2
    XLogP34.1
    Hydrogen Bond Donor Count3
    Hydrogen Bond Acceptor Count5
    Rotatable Bond Count5
    Exact Mass509.08627 g/mol
    Monoisotopic Mass509.08627 g/mol
    Topological Polar Surface Area86.4 Ų
    Heavy Atom Count33
    Formal Charge0
    Complexity746
    Isotope Atom Count0
    Defined Atom Stereocenter Count0
    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

    Ripretinib is indicated to treat adults diagnosed with advanced gastrointestinal stromal tumor (GIST) who have had prior therapy with at least 3 kinase inhibitors, including with [imatinib].

    FDA Label

    Qinlock is indicated for the treatment of adult patients with advanced gastrointestinal stromal tumour (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib.

    5 Pharmacology and Biochemistry
    5.1 Pharmacology

    As a broad-spectrum kinase inhibitor, ripretinib inhibits various gene mutations, increasing progression-free survival in patients with advanced gastrointestinal stromal tumors (GIST). It is effective in treating mutations that are resistant to chemotherapy with other kinase inhibitors, such as imatinib. Ripretinib has the propensity to cause cardiac dysfunction and new primary cutaneous malignancy. It is important to measure cardiac ejection fraction before and during treatment as well as to perform regular dermatological assessments.

    5.2 FDA Pharmacological Classification
    5.2.1 Active Moiety
    RIPRETINIB
    5.2.2 FDA UNII
    9XW757O13D
    5.2.3 Pharmacological Classes
    Cytochrome P450 2C8 Inhibitors [MoA]; Kinase Inhibitor [EPC]; P-Glycoprotein Inhibitors [MoA]; Platelet-derived Growth Factor alpha Receptor Inhibitors [MoA]; Stem Cell Factor (KIT) Receptor Inhibitors [MoA]; Breast Cancer Resistance Protein Inhibitors [MoA]
    5.3 ATC Code

    L01

    L - Antineoplastic and immunomodulating agents

    L01 - Antineoplastic agents

    L01E - Protein kinase inhibitors

    L01EX - Other protein kinase inhibitors

    L01EX19 - Ripretinib

    5.4 Absorption, Distribution and Excretion

    Absorption

    Ripretinib is absorbed in the gastrointestinal tract and Tmax is achieved in 4 hours, with steady-state concentrations reached within 14 days.

    Route of Elimination

    Ripretinib is 34% excreted in the feces and 0.2% excreted in the urine.

    Volume of Distribution

    The mean volume of distribution of ripretinib is 307 L.

    Clearance

    The mean apparent clearance of ripretinib is 15.3 L/hour.

    5.5 Metabolism/Metabolites

    Ripretinib is metabolized by the CYP3A subfamily of enzymes with contributions from CYP2D6 and CYP2E1 to its active metabolite, DP-5439.

    5.6 Biological Half-Life

    The average half-life of ripretinib is 14.8 hours.

    5.7 Mechanism of Action

    Protein kinases play important roles in cellular function, and their dysregulation can lead to carcinogenesis. Ripretinib inhibits protein kinases including wild type and mutant platelet-derived growth factor receptor A (PDGFRA) and KIT that cause the majority of gastrointestinal stromal tumor (GIST). In vitro, ripretinib has been shown to inhibit PDGFRB, BRAF, VEGF, and TIE2 genes. Ripretinib binds to KIT and PDGFRA receptors with mutations on the exons 9, 11, 13, 14, 17 and 18 (for KIT mutations), and exons 12, 14 and 18 (for PDGFRA mutations). The switch pocket of a protein kinase is normally bound to the activation loop, acting as an on-off switch of a kinase. Ripretinib boasts a unique dual mechanism of action of binding to the kinase switch pocket as well as the activation loop, thereby turning off the kinase and its ability to cause dysregulated cell growth.