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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
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 Weight 454.9 g/mol
Molecular Formula C22H19ClN4O5
XLogP34
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count7
Rotatable Bond Count6
Exact Mass454.1043974 g/mol
Monoisotopic Mass454.1043974 g/mol
Topological Polar Surface Area108 Ų
Heavy Atom Count32
Formal Charge0
Complexity631
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

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.


USDMF

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Synthon Bv

Netherlands

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Synthon Bv

Netherlands
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GDUFA

DMF Review : Complete

Rev. Date : 2024-10-09

Pay. Date : 2024-09-09

DMF Number : 40289

Submission : 2024-09-10

Status : Active

Type : II

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NDC API

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TIVOZANIB HYDROCHLORIDE

NDC Package Code : 51557-100

Start Marketing Date : 2021-03-10

End Marketing Date : 2025-12-31

Dosage Form (Strength) : POWDER (1kg/kg)

Marketing Category : BULK INGREDIENT

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Valary Lab Private Limited

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Valary Lab Private Limited

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TIVOZANIB HYDROCHLORIDE

NDC Package Code : 81955-0023

Start Marketing Date : 2021-03-10

End Marketing Date : 2025-12-31

Dosage Form (Strength) : POWDER (1kg/kg)

Marketing Category : BULK INGREDIENT

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Listed Suppliers

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Suanfarma

Spain
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Tivozanib

About the Company : Suanfarma founded in 1993, is a B2B life science partner committed to health & innovation by developing, manufacturing, & distributing high-quality APIs for the pharmaceutical indu...

Suanfarma founded in 1993, is a B2B life science partner committed to health & innovation by developing, manufacturing, & distributing high-quality APIs for the pharmaceutical industry innovatively & sustainably. Backed by a robust global network of 12 strategically located local offices, we cater to the needs of over 400 active customers in 70+ countries. At Suanfarma we offer our CDMO capacity for fermentation & chemical synthesis projects, offering a One Stop Shop service with a solid track record, & which allows us to achieve success in the development, scaling, manufacturing, & commercialization of an API, either innovative or generic.
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Tivozanib

About the Company : Founded in 1935, TAPI Technology & API Services has a long-standing tradition of advancing health through innovation and dedication. Today, we proudly build upon this legacy, drivi...

Founded in 1935, TAPI Technology & API Services has a long-standing tradition of advancing health through innovation and dedication. Today, we proudly build upon this legacy, driving progress in the pharmaceutical industry. Leveraging our extensive experience and world-class expertise, we deliver one of the most comprehensive API portfolios in the industry. Additionally, we provide tailored CDMO services, harnessing our proficiency in diverse technologies to meet our partners' unique needs, ensuring flexibility and excellence in every project.
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Arevipharma

Germany
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Arevipharma

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Tivozanib

About the Company : Arevipharma GmbH is a modern manufacturer of active pharmaceutical ingredients and intermediates with more than 140 years of expertise. Our customers are generic and research-based...

Arevipharma GmbH is a modern manufacturer of active pharmaceutical ingredients and intermediates with more than 140 years of expertise. Our customers are generic and research-based pharmaceutical companies on five continents. Our business partners recognise us as a competent, reliable and efficient company that is distinguished by individual service and an innovative character. The company’s 140 year history is based on the knowledge, skills, commitment and loyalty of its employees. Arevipharma also feels committed to its owners and investors. Due to the consistent expansion of new technologies,
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Tivozanib

About the Company : Beijing Sjar Technology Development Co., Ltd. founded in 2014, it is a high-tech enterprise which specialized in the research and development of active pharmaceutical ingredients a...

Beijing Sjar Technology Development Co., Ltd. founded in 2014, it is a high-tech enterprise which specialized in the research and development of active pharmaceutical ingredients and their intermediates, electronic chemical materials and intermediates, large-scale production, sales and services, and provide customized synthetic services according to customer requirements. Sjar-Tech locates in Beijing Economic and Technological Development Zone, has its own R&D and development laboratory. Sjar-Tech has set up a R&D team with rich experience and strong technical strength, most of the practitioners have more than ten years' experience.
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Tivozanib

About the Company : Hope Chem is dedicated to manufacturing, marketing, and CMO service of Active Pharmaceutical Ingredients (APIs), Intermediates, and Specialty Chemicals since the year 2010. Current...

Hope Chem is dedicated to manufacturing, marketing, and CMO service of Active Pharmaceutical Ingredients (APIs), Intermediates, and Specialty Chemicals since the year 2010. Currently, they have exclusive partnerships with multiple, state-of-the-art and GMP-compliant manufacturers in China and abroad to service our esteemed partners for competitive, long-term & stable supplies. The main products are APIs and intermediates of antiviral drug substances and anti-inflammatory, analgesic, and non-steroidal pharmaceuticals.
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ABOUT THIS PAGE

Tivozanib Manufacturers

A Tivozanib manufacturer is defined as any person or entity involved in the manufacture, preparation, processing, compounding or propagation of Tivozanib, including repackagers and relabelers. The FDA regulates Tivozanib manufacturers to ensure that their products comply with relevant laws and regulations and are safe and effective to use. Tivozanib API Manufacturers are required to adhere to Good Manufacturing Practices (GMP) to ensure that their products are consistently manufactured to meet established quality criteria.

click here to find a list of Tivozanib manufacturers with USDMF, JDMF, KDMF, CEP, GMP, COA and API Price related information on PhamaCompass.

Tivozanib Suppliers

A Tivozanib supplier is an individual or a company that provides Tivozanib active pharmaceutical ingredient (API) or Tivozanib finished formulations upon request. The Tivozanib suppliers may include Tivozanib API manufacturers, exporters, distributors and traders.

click here to find a list of Tivozanib suppliers with USDMF, JDMF, KDMF, CEP, GMP, COA and API Price related information on PharmaCompass.

Tivozanib USDMF

A Tivozanib DMF (Drug Master File) is a document detailing the whole manufacturing process of Tivozanib active pharmaceutical ingredient (API) in detail. Different forms of Tivozanib DMFs exist exist since differing nations have different regulations, such as Tivozanib USDMF, ASMF (EDMF), JDMF, CDMF, etc.

A Tivozanib DMF submitted to regulatory agencies in the US is known as a USDMF. Tivozanib USDMF includes data on Tivozanib's chemical properties, information on the facilities and procedures used, and details about packaging and storage. The Tivozanib USDMF is kept confidential to protect the manufacturer’s intellectual property.

click here to find a list of Tivozanib suppliers with USDMF on PharmaCompass.

Tivozanib NDC

National Drug Code is a comprehensive database maintained by the FDA that contains information on all drugs marketed in the US. This directory includes information about finished drug products, unfinished drug products, and compounded drug products, including those containing Tivozanib as an active pharmaceutical ingredient (API).

Finished drug products

The FDA updates the NDC directory daily. The NDC numbers for Tivozanib API and other APIs are published in this directory by the FDA.

Unfinished drugs

The NDC unfinished drugs database includes product listing information submitted for all unfinished drugs, such as active pharmaceutical ingredients (APIs), drugs intended for further processing and bulk drug substances for compounding.

Pharmaceutical companies that manufacture Tivozanib as an active pharmaceutical ingredient (API) must furnish the FDA with an updated record of all drugs that they produce, prepare, propagate, compound, or process for commercial distribution in the US at their facilities.

Compounded drug products

The NDC directory also contains data on finished compounded human drug products that contain Tivozanib and are produced by outsourcing facilities. While these outsourcing facilities are not mandated to assign a Tivozanib NDC to their finished compounded human drug products, they may choose to do so.

click here to find a list of Tivozanib suppliers with NDC on PharmaCompass.

Tivozanib GMP

Tivozanib Active pharmaceutical ingredient (API) is produced in GMP-certified manufacturing facility.

GMP stands for Good Manufacturing Practices, which is a system used in the pharmaceutical industry to make sure that goods are regularly produced and monitored in accordance with quality standards. The FDA’s current Good Manufacturing Practices requirements are referred to as cGMP or current GMP which indicates that the company follows the most recent GMP specifications. The World Health Organization (WHO) has its own set of GMP guidelines, called the WHO GMP. Different countries can also set their own guidelines for GMP like China (Chinese GMP) or the EU (EU GMP).

PharmaCompass offers a list of Tivozanib GMP manufacturers, exporters & distributors, which can be sorted by USDMF, JDMF, KDMF, CEP (COS), WC, API price, and more, enabling you to easily find the right Tivozanib GMP manufacturer or Tivozanib GMP API supplier for your needs.

Tivozanib CoA

A Tivozanib CoA (Certificate of Analysis) is a formal document that attests to Tivozanib's compliance with Tivozanib specifications and serves as a tool for batch-level quality control.

Tivozanib CoA mostly includes findings from lab analyses of a specific batch. For each Tivozanib CoA document that a company creates, the USFDA specifies specific requirements, such as supplier information, material identification, transportation data, evidence of conformity and signature data.

Tivozanib may be tested according to a variety of international standards, such as European Pharmacopoeia (Tivozanib EP), Tivozanib JP (Japanese Pharmacopeia) and the US Pharmacopoeia (Tivozanib USP).

Inform the supplier about your product requirements, specifying if you need a product with particular monograph like EP (Ph. Eur.), USP, JP, BP, or any other quality. In addition, clarify whether you need hydrochloride (HCl), anhydricum, base, micronisatum or a specific level of purity. To find reputable suppliers, utilize the filters and select those certified by GMP, FDA, or any other certification as per your requirement.
For your convenience, we have listed synonyms and CAS numbers to help you find the best supplier. The use of synonyms and CAS numbers can be helpful in identifying potential suppliers, but it is crucial to note that they might not always indicate the exact same product. It is important to confirm the product details with the supplier before making a purchase to ensure that it meets your requirements.
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