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Ripretinib

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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

Ripretinib

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 Formula	C₂₄H₂₁BrFN₅O₂
Molecular Weight	510.4 g/mol
XLogP3	4.1
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	5
Exact Mass	509.08627 g/mol
Monoisotopic Mass	509.08627 g/mol
Topological Polar Surface Area	86.4 Å²
Heavy Atom Count	33
Formal Charge	0
Complexity	746
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
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

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.

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