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Tivozanib

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Chemistry

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Also known as: 475108-18-0, Av-951, Tivozanib (av-951), Krn-951, Av 951, Av951

Molecular Formula

C₂₂H₁₉ClN₄O₅

Molecular Weight

454.9 g/mol

InChI Key

SPMVMDHWKHCIDT-UHFFFAOYSA-N

FDA UNII

172030934T

Tivozanib is an orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3 with potential antiangiogenic and antineoplastic activities. Tivozanib binds to and inhibits VEGFRs 1, 2 and 3, which may result in the inhibition of endothelial cell migration and proliferation, inhibition of tumor angiogenesis and tumor cell death. VEGFR tyrosine kinases, frequently overexpressed by a variety of tumor cell types, play a key role in angiogenesis.

Tivozanib is a Kinase Inhibitor. The mechanism of action of tivozanib is as a Tyrosine Kinase Inhibitor.

1 2D Structure

Tivozanib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea

2.1.2 InChI

InChI=1S/C22H19ClN4O5/c1-12-8-21(27-32-12)26-22(28)25-16-5-4-13(9-15(16)23)31-18-6-7-24-17-11-20(30-3)19(29-2)10-14(17)18/h4-11H,1-3H3,(H2,25,26,27,28)

2.1.3 InChI Key

SPMVMDHWKHCIDT-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC1=CC(=NO1)NC(=O)NC2=C(C=C(C=C2)OC3=C4C=C(C(=CC4=NC=C3)OC)OC)Cl

2.2 Other Identifiers

2.2.1 UNII

172030934T

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Av 951

2. Av-951

3. Av951 Cpd

4. Fotivda

5. Krn 951

6. Krn-951

7. Krn951

2.3.2 Depositor-Supplied Synonyms

1. 475108-18-0

2. Av-951

3. Tivozanib (av-951)

4. Krn-951

5. Av 951

6. Av951

7. 1-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea

8. Krn951

9. Fotivda

10. Kil8951

11. Krn 951

12. N-[2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-n'-(5-methyl-3-isoxazolyl)urea

13. Kil-8951

14. Chembl1289494

15. Av-951;krn951

16. 1-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea

17. 1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea

18. 172030934t

19. 1-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)-oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea

20. N-(2-chloro-4-((6,7-dimethoxy-4-quinolyl)oxy)phenyl)-n'-(5-methyl-3-isoxazolyl)urea

21. Urea, N-(2-chloro-4-((6,7-dimethoxy-4-quinolinyl)oxy)phenyl)-n'-(5-methyl-3-isoxazolyl)-

22. Tivozanib [usan]

23. Asp-4130

24. Tivozanib [usan:inn]

25. 4ase

26. N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-n'-(5-methyl-3-isoxazolyl)urea

27. Av9

28. Unii-172030934t

29. Av-951,tivozanib

30. Tivozanib(av-951)

31. Tivozanib [inn]

32. Av951 Cpd

33. Tivozanib (usan/inn)

34. Tivozanib - Av-951

35. Tivozanib [who-dd]

36. Mls006011287

37. Schembl172883

38. Gtpl6058

39. Chebi:91327

40. Dtxsid20963865

41. Ex-a472

42. Hms3229o09

43. Hms3244c19

44. Hms3244c20

45. Hms3244d19

46. Hms3265a11

47. Hms3265a12

48. Hms3265b11

49. Hms3265b12

50. Hms3654g22

51. Hms3745c05

52. Amy39975

53. Bcp01980

54. Zinc1489430

55. Vegfr Tyrosine Kinase Inhibitor Iv

56. Bdbm50331095

57. Mfcd15146788

58. Nsc758007

59. Nsc800952

60. S1207

61. Akos022177607

62. Av951 (krn951, Tivozanib)

63. Bcp9000343

64. Ccg-206805

65. Cs-0103

66. Db11800

67. Ex-8600

68. Nsc-758007

69. Nsc-800952

70. Pb28569

71. Ncgc00249390-01

72. Ncgc00249390-05

73. Ncgc00249390-12

74. Ac-24702

75. As-16997

76. Bt160380

77. Hy-10977

78. Smr004703037

79. Ft-0700315

80. Sw219364-1

81. A24970

82. D09683

83. 108k180

84. J-502964

85. Q7810457

86. Brd-k53414658-001-01-7

87. 1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methyl-1,2-oxazol-3-yl)urea

88. N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)-oxy]phenyl}-n'-(5-methyl-3-isoxazolyl)urea

89. 1-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea;av-951

90. 1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-[(3e)-5-methylisoxazol-3(2h)-ylidene]urea

91. N-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-n'-(5-methylisoxazol-3-yl)urea

2.4 Create Date

2006-10-25

3 Chemical and Physical Properties

Molecular Formula	C₂₂H₁₉ClN₄O₅
Molecular Weight	454.9 g/mol
XLogP3	4
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	6
Exact Mass	454.1043974 g/mol
Monoisotopic Mass	454.1043974 g/mol
Topological Polar Surface Area	108 Å²
Heavy Atom Count	32
Formal Charge	0
Complexity	631
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

Tivozanib is approved in the USA for the treatment of relapsed or refractory renal cell carcinoma in adult patients who have undergone two or more systemic therapies. In the UK and other countries, is indicated as first line therapy of adults with advanced renal cell carcinoma (RCC) and VEGFR and mTOR pathway inhibitor-nave patients after disease progression following one previous treatment with cytokine therapy for advanced disease.

Fotivda is indicated for the first line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-nave following disease progression after one prior treatment with cytokine therapy for advanced RCC.

Treatment of advanced renal cell carcinoma.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Tivozanib inhibits growth factor receptors, treating renal cell carcinoma. In mice and rats, tivozanib inhibits tumour angiogenesis, tumour growth, and vascular permeability. Tivozanib was shown to frequently cause hypertension in clinical trials; hypertension must be managed before initiating therapy. Cardiac QT segment prolongation was reported in a tivozanib cardiac safety study, however the reactions were not considered clinically serious. In clinical studies, levels of serum soluble VEGFR2 (sVEGFR2) decreased with time and this effect increased with tivozanib exposure, and sVEGFR2 may serve as a pharmacodynamic marker of VEGFR inhibition.

5.2 MeSH Pharmacological Classification

Protein Kinase Inhibitors

Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

TIVOZANIB

5.3.2 FDA UNII

172030934T

5.3.3 Pharmacological Classes

Tyrosine Kinase Inhibitors [MoA]; Kinase Inhibitor [EPC]

5.4 ATC Code

L01EK03

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EK - Vascular endothelial growth factor receptor (vegfr) tyrosine kinase inhibitors

L01EK03 - Tivozanib

5.5 Absorption, Distribution and Excretion

Absorption

The median Tmax of tivozanib is 10 hours, however, can range from 3 to 24 hours. A pharmacokinetic study in 8 healthy subjects revealed a Cmax and AUC for radiolabeled tivozanib of 12.1 5.67 ng/mL and 1084 417.0 ngh/mL, respectively. Steady-state tivozanib concentrations are achieved at concentrations 6-7 times higher the normal dose.

Route of Elimination

Tivozanib is primarily excreted in the feces. After oral ingestion of a radiolabeled 1.34 mg dose of tivozanib in healthy volunteers, 79% of the administered dose was found in the feces (with 26% unchanged) and 12% was found in the urine solely as metabolites.

Volume of Distribution

Tivozanib has an apparent volume of distribution (V/F) of 123 L.

Clearance

The apparent clearance (CL/F) of tivozanib is approximately 0.75 L/h.

5.6 Metabolism/Metabolites

Tivozanib is primarily metabolized by CYP3A4. After oral ingestion of a radiolabeled 1.34 mg dose of tivozanib in healthy volunteers, unchanged tivozanib accounted for 90% of the radioactive drug detected in serum.

5.7 Biological Half-Life

The half-life of tivozanib is about 111 hours according to prescribing information. Information from clinical studies reveals a half-life of 4-5 days.

5.8 Mechanism of Action

The VHL mutation-HIF upregulation-VEGF transcription is the main pathway implicated in the growth of renal cell carcinoma. Vascular endothelial growth factor receptors (VEGFR receptors) are important targets for tyrosine kinase inhibitors, which halt the growth of tumours. Tivozanib is a tyrosine kinase inhibitor that exerts its actions by inhibiting the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3 and inhibits other kinases such as c-kit and platelet derived growth factor beta (PDGFR ). The above actions inhibit tumour growth and progression, treating renal cell carcinoma.

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