| Identification | Back Directory | [Name]
N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N'-(5-methyl-3-isoxazolyl)urea | [CAS]
475108-18-0 | [Synonyms]
AV951
AV-951
KRN-951
Tivozanib
AV-951(Tivozanib)
Tivozanib(AV951,KRN951)
1-(2-Chloro-4-(6,7-diMethoxyquinolin-4-yloxy)phenyl)-3-(5-Methylisoxazol-3-yl)urea
N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N'-(5-methyl-3-isoxazolyl)urea
N-{[(2R)-2,3-dihydroxypropyl]oxy}-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)aMino]benzaMide
Krn-951
Urea, N-(2-chloro-4-((6,7-diMethoxy-4-quinolinyl)oxy)phenyl)-N'-(5-Methyl-3-isoxazolyl)-
N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N'-(5-methyl-3-isoxazolyl)urea Tivozanib (AV-951) | [Molecular Formula]
C22H19ClN4O5 | [MDL Number]
MFCD15146788 | [MOL File]
475108-18-0.mol | [Molecular Weight]
454.86 |
| Chemical Properties | Back Directory | [Melting point ]
>202°C (dec.) | [Boiling point ]
550.4±50.0 °C(Predicted) | [density ]
1.421 | [storage temp. ]
Refrigerator | [solubility ]
DMSO (Slightly), Methanol (Slightly, Heated) | [form ]
White powder. | [pka]
11.74±0.70(Predicted) | [color ]
Pale Beige to Light Brown |
| Hazard Information | Back Directory | [Uses]
Tivozanib also known as AV-951 is an orally bioavailable potent VEGFR-1, 2 and 3, c-Kit and PDGFR inhibitor with IC50 of 0.21, 0.16, 0.24, 1.63 and 1.72 nM, respectively. | [Uses]
Tivozanib is known as an oral VEGF receptor tyrosine kinase inhibitor, exhibiting antitumor effects towards renal cell carcinoma.. Tivozanib suppresses angiogenesis by selectively inhibiting against v
ascular endothelial growth factor. | [Definition]
ChEBI: 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea is an aromatic ether. | [Biological Activity]
tivozanib is an inhibitor of tyrosine kinase with ic50 value of 160 pmol/l against vegfr-2 [1].tivozanib is a quinoline-urea derivative. as a 2nd generation tki, it has picomolar potency against vegfr-1, -2 and -3, and minimal c-kit inhibition. among this, tivozanib has demonstrated a vegfr-2 potency 2 orders of magnitude greater than sunitinib, sorafenib or pazopanib and a lower relative extent of off-target inhibition [1]. tivozanib also shows to inhibit phosphorylation of the kinases pdgfr? and c-kit at nanomolar level in cellular assays [2].tivozanib has shown antitumor activity in rcc xenograft models in addition to several other solid tumor models leading to its evaluation in clinical testing. the safety and efficacy of tivozanib has been evaluated in several phase i and phase ii trials. to compare the front-line use of tivozanib to sorafenib, a pivotal randomized phase iii trial has also been reported [3]. | [Mechanism of action]
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 β). | [Side effects]
- diarrhea
- nausea
- vomiting
- fatigue
- loss of appetite
- weight loss
- voice hoarseness
- back pain
- mouth sores
- cough
- shortness of breath
| [Synthesis]
The synthesis of Tivozanib is as follows:
Phenyl chlorocarbonate (601 g) was added dropwise to 3-amino-5-methylisoxazole (377 g), pyridine (1215 g), and N,N-dimethylacetamide (4 L) at 0°C, and the mixture was stirred at 20°C for 2 hr. 4-[(4-Amino-3-chlorophenol)oxy]-6,7-dimethoxyquinoline (847 g) was added to the reaction solution, and the mixture was stirred at 80°C for 5 hr. The reaction solution was cooled to 5°C. Thereafter, methanol (8.5 L) and water (8.5 L) were added thereto, and the mixture was neutralized with an aqueous sodium hydroxide solution. The resultant precipitate was collected by filtration, and the filtered product was slurried in water (8.5 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give Tivozanib (1002 g, yield 86.1%).
 | [target]
VEGFR-2 | [References]
[1] m.n. fishman, s. srinivas, r.j. hauke, r.j. amato, b. esteves, m.m. cotreau, a.l. strahs, w.j. slichenmyer, p. bhargava, f.f. kabbinavar. phase ib study of tivozanib (av-951) in combination with temsirolimus in patients with renal cell carcinoma. european journal of cancer. 2013(49):2841-2850.
[2] viktor grunwald, axel stuart merseburger. the progression free survival-plateau with vascular endothelial growth factor receptor inhibitors – is there more to come? european journal of cancer. 2013(49):2504-2511.
[3] c lance cowey. profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma. drug design, development and therapy. 2013 (7): 519-527. |
| Questions And Answer | Back Directory | [Description]
Tivozanib (AV-951) is a potent and selective VEGFR inhibitor for VEGFR1/2/3 with IC50 of 30 nM/6.5 nM/15 nM, and also inhibits PDGFR and c-Kit, low activity observed against FGFR-1, Flt3, c-Met, EGFR and IGF-1R. Phase 3. | [In vitro]
AV-951 is a novel quinoline-urea derivative. AV-951 blocks VEGF-dependent activation of mitogen-activated protein kinases and proliferation of endothelial cells. | [In vivo]
In vivo studies show that AV-951 also decreases the micro vessel density and suppresses VEGFR2 phosphorylation levels in tumor xenografts, especially at a concentration of 1mg/kg (p.o. administration). AV-951 shows almost complete inhibition of tumor xenografts growth (TGI>85%) in athymic rats. Another study in rat peritoneal disseminated tumor model shows that AV-951 could prolong the survival of the tumor-bearing rats with the MST of 53.5 days. AV-951 displays antitumor activity against many human tumor xenografts including lung, breast, colon, ovarian, pancreas and prostate cancer. |
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