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    Regorafenib

    ACTIVE PHARMA INGREDIENTS

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    2D Structure
    Also known as: 755037-03-7, Bay 73-4506, Stivarga, 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-n-methylpicolinamide, Regorafenibum, Regorafenib (bay 73-4506)
    Molecular Formula
    C21H15ClF4N4O3
    Molecular Weight
    482.8  g/mol
    InChI Key
    FNHKPVJBJVTLMP-UHFFFAOYSA-N
    FDA UNII
    24T2A1DOYB
    Regorafenib is the anhydrous form of regorafenib, an orally bioavailable small molecule with potential antiangiogenic and antineoplastic activities. Regorafenib binds to and inhibits vascular endothelial growth factor receptors (VEGFRs) 2 and 3, and Ret, Kit, PDGFR and Raf kinases, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation. VEGFRs are receptor tyrosine kinases that play important roles in tumor angiogenesis; the receptor tyrosine kinases RET, KIT, and PDGFR, and the serine/threonine-specific Raf kinase are involved in tumor cell signaling.
    Regorafenib is a Kinase Inhibitor. The mechanism of action of regorafenib is as a Protein Kinase Inhibitor, and Cytochrome P450 2C9 Inhibitor.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
    2.1.2 InChI
    InChI=1S/C21H15ClF4N4O3/c1-27-19(31)18-10-13(6-7-28-18)33-12-3-5-17(16(23)9-12)30-20(32)29-11-2-4-15(22)14(8-11)21(24,25)26/h2-10H,1H3,(H,27,31)(H2,29,30,32)
    2.1.3 InChI Key
    FNHKPVJBJVTLMP-UHFFFAOYSA-N
    2.1.4 Canonical SMILES
    CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F
    2.2 Other Identifiers
    2.2.1 UNII
    24T2A1DOYB
    2.3 Synonyms
    2.3.1 MeSH Synonyms

    1. 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)-3-fluorophenoxy)-n-methylpyridine-2-carboxamide

    2. Bay 73-4506

    3. Bay-73-4506

    4. Bay73-4506

    5. Stivarga

    2.3.2 Depositor-Supplied Synonyms

    1. 755037-03-7

    2. Bay 73-4506

    3. Stivarga

    4. 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-n-methylpicolinamide

    5. Regorafenibum

    6. Regorafenib (bay 73-4506)

    7. Bay73-4506

    8. Bay-73-4506

    9. 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide

    10. Regorafenib-13c-d3

    11. 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-n-methylpyridine-2-carboxamide

    12. 24t2a1doyb

    13. Chembl1946170

    14. Chebi:68647

    15. Bay-734506

    16. Stivarga (tn)

    17. 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)-3-fluorophenoxy)-n-methylpyridine-2-carboxamide

    18. Regorafenib [inn]

    19. Regorafenib [usan:inn]

    20. Unii-24t2a1doyb

    21. Fluoro-sorafenib

    22. 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl}amino)-3-fluorophenoxy)-n-methylpyridine-2-carboxamide

    23. Regorafenib [mi]

    24. Regorafenib (usan/inn)

    25. Regorafenib [vandf]

    26. Regorafenib Anhydrous

    27. Regorafenib [who-dd]

    28. Mls006010303

    29. Regorafenib Crystalline Form I

    30. Schembl432230

    31. Regorafenib,bay 73-4506

    32. Gtpl5891

    33. Dtxsid60226441

    34. Ex-a058

    35. Regorafenib - Bay 73-4506

    36. Bcpp000352

    37. Hms3654k16

    38. Hms3672e15

    39. Bcp02105

    40. Bkd17855

    41. Zinc6745272

    42. Bdbm50363397

    43. Mfcd16038047

    44. Nsc763932

    45. Nsc800865

    46. S1178

    47. Akos015951107

    48. Am81251

    49. Bay 734506

    50. Bcp9000384

    51. Ccg-269571

    52. Cs-0170

    53. Db08896

    54. Nsc-763932

    55. Nsc-800865

    56. Sb16819

    57. Ncgc00263138-01

    58. Ncgc00263138-13

    59. Ncgc00263138-19

    60. 2-pyridinecarboxamide,4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-n-methyl-

    61. 835621-08-4

    62. Ac-25075

    63. Ac-31116

    64. As-16304

    65. Hy-10331

    66. Smr004701370

    67. Ft-0674338

    68. R0142

    69. Sw218097-2

    70. Cas:835621-07-3;regorafenib Hydrochloride

    71. Regorafenib (bay73-4506,fluoro-sorafenib)

    72. A25020

    73. D10138

    74. Ab01565826_02

    75. Sr-01000941571

    76. Q3891664

    77. Sr-01000941571-1

    78. Brd-k16730910-001-02-4

    79. 2-pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-n-methyl-

    80. 4-[4-({[4-chloro-3-(trifluoromethy)phenyl]carbamoyl}amino)-3-fluorophenoxy]-1-methylpyridine-2-carboxamide

    81. 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic Acid Methylamide

    82. Regorafenib;1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea

    2.4 Create Date
    2006-10-26
    3 Chemical and Physical Properties
    Molecular Weight 482.8 g/mol
    Molecular Formula C21H15ClF4N4O3
    XLogP34.2
    Hydrogen Bond Donor Count3
    Hydrogen Bond Acceptor Count8
    Rotatable Bond Count5
    Exact Mass482.0768807 g/mol
    Monoisotopic Mass482.0768807 g/mol
    Topological Polar Surface Area92.4 Ų
    Heavy Atom Count33
    Formal Charge0
    Complexity686
    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 Information
    1 of 2  
    Drug NameStivarga
    PubMed HealthRegorafenib (By mouth)
    Drug ClassesAntineoplastic Agent
    Drug LabelStivarga (regorafenib) has the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Regorafenib has the following structural formula:Regorafenib is a monohydrate and...
    Active IngredientRegorafenib
    Dosage FormTablet
    Routeoral; Oral
    Strength40mg
    Market StatusPrescription
    CompanyBayer Healthcare Pharms; Bayer Hlthcare

    2 of 2  
    Drug NameStivarga
    PubMed HealthRegorafenib (By mouth)
    Drug ClassesAntineoplastic Agent
    Drug LabelStivarga (regorafenib) has the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Regorafenib has the following structural formula:Regorafenib is a monohydrate and...
    Active IngredientRegorafenib
    Dosage FormTablet
    Routeoral; Oral
    Strength40mg
    Market StatusPrescription
    CompanyBayer Healthcare Pharms; Bayer Hlthcare

    4.2 Drug Indication

    Regorafenib is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Regorafenib is also indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumour (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. Regorafenib is also indicated for the treatment of patients with hepatocellular carcinoma (HCC) previously treated with sorafenib.

    FDA Label

    Stivarga is indicated as monotherapy for the treatment of adult patients with:

    - metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies - these include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy;

    - unresectable or metastatic gastrointestinal stromal tumors (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib;

    - hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

    5 Pharmacology and Biochemistry
    5.1 FDA Pharmacological Classification
    5.1.1 Active Moiety
    REGORAFENIB
    5.1.2 FDA UNII
    24T2A1DOYB
    5.1.3 Pharmacological Classes
    Kinase Inhibitor [EPC]; Protein Kinase Inhibitors [MoA]; Cytochrome P450 2C9 Inhibitors [MoA]
    5.2 ATC Code

    L01EX05

    L01XE21

    S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

    L - Antineoplastic and immunomodulating agents

    L01 - Antineoplastic agents

    L01E - Protein kinase inhibitors

    L01EX - Other protein kinase inhibitors

    L01EX05 - Regorafenib

    5.3 Absorption, Distribution and Excretion

    Absorption

    Cmax = 2.5 g/mL; Tmax = 4 hours; AUC = 70.4 g*h/mL; Cmax, steady-state = 3.9 g/mL; AUC, steady-state = 58.3 g*h/mL; The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.

    Route of Elimination

    Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.

    Volume of Distribution

    Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval.

    5.4 Metabolism/Metabolites

    Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively). Regorafenib is an inhibitor of P-glycoprotein, while its active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) are substrates of P-glycoprotein.

    5.5 Biological Half-Life

    Regorafenib, 160 mg oral dose = 28 hours (14 - 58 hours); M2 metabolite, 160 mg oral dose = 25 hours (14-32 hours); M5 metabolite, 160 mg oral dose = 51 hours (32-72 hours);

    5.6 Mechanism of Action

    Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.