Linifanib (ABT-869) Chemical Properties

Melting point:

180-183°C (dec.)

Boiling point:

542.2±50.0 °C(Predicted)

Density 

1.424

storage temp. 

-20°C Freezer

solubility 

DMSO, Methanol

form 

Brown powder.

pka

13.30±0.70(Predicted)

color 

Beige

InChI

InChI=1S/C21H18FN5O/c1-12-5-10-16(22)18(11-12)25-21(28)24-14-8-6-13(7-9-14)15-3-2-4-17-19(15)20(23)27-26-17/h2-11H,1H3,(H3,23,26,27)(H2,24,25,28)

InChIKey

MPVGZUGXCQEXTM-UHFFFAOYSA-N

SMILES

N(C1=CC=C(C2=CC=CC3=C2C(N)=NN3)C=C1)C(NC1=CC(C)=CC=C1F)=O

Safety Information

HS Code 

2933998090

Linifanib (ABT-869) Usage And Synthesis

Chemical Properties

Beige Solid

Uses

Linifanib (ABT-869) is a novel, potent ATP-competitive RTK inhibitor for KDR, CSF-1R, Flt-1, Flt-3 and PDGFRβ with IC50 of 4 nM, 3 nM, 3 nM, 3 nM, and 66 nM respectively.

Uses

Linifanib (ABT 869) is an oral tyrosine kinase inhibitor with antineoplasic activity. As a dual inhibitor, Linifanib, is being tested on several different cancers.

Definition

ChEBI: A member of the class of ureas that is urea in which one of the nitrogens is substituted by a 2-fluoro-5-methylphenyl group, while the other nitrogen is substituted by a p-(3-amino-1H-indazol-4-yl)phenyl group. It is a poten , selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases.

Biological Activity

linifanib (abt-869) is an effective atp-competitive tyrosine kinase inhibitor against the platelet-derived growth factor (pdgf) receptor and the vascular endothelial growth factor receptor (vegfr) families, including constitutively active fms-like receptor tyrosine kinase 3 (flt3) [1][2]. it is of ic50 values of 0.55 nmol/l and 6 μmol/l to the cell growth in ba/f3 flt3 itd mutant cells and in ba/f3 flt3 wt cells, respectively [1].flt3 is important in controlling the proliferation and differentiation of hematopoietic cells. patients with acute myeloid leukemia (aml) showed activating mutations in flt3. these mutations caused abnormal cell proliferation [1].linifanib at a concentration of 10 nmol/l induced apoptosis in internal tandem duplication (itd) mutant cells, but showed no effect in wt cells. treatment with linifanib did not differentiate wt cells from flt3 mutant cells with mutation at d835v, in inhibiting proliferation or reducing cell viability. in ba/f3 flt3 itd cell lines, linifanib at a concentration of 10 nmol/l, effectively inhibited the phosphorylation of flt3. 10 nmol/l linifanib reduced the phosphorylation of akt at ser473 [1].daily orally treatment with linifanib by gavage in nod/scid mice with itd mutant cell decreased the leukemia progression rate compared with the control. on day 7, itd mutant cells showed rapid progression in control mice, whereas linifanib-treated mice showed no detectable disease. in addition, daily linifanib-treated mice with itd mutant cells showed significantly longer (p < 0.01) survival duration than control mice with itd mutant cells only [1].

Synthesis

The general procedure for the synthesis of 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea from 3-amino-4-iodoindazole and N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea was carried out as follows: the compound of formula VI ( 10.6 g, 28.6 mmol) was added to a reaction flask, followed by 3-amino-4-iodoindazole (8.1 g, 31.3 mmol), sodium carbonate (7.6 g, 71.7 mmol), ethanol (100 mL), and water (100 mL). After mixing with stirring at room temperature, PdCl2 (dppf) (0.4 g, 0.6 mmol) was added and the reaction mixture was heated to reflux. After refluxing the reaction for 8 hours, ethanol was removed by distillation under reduced pressure. Ethyl acetate (150 mL) and 20% aqueous ammonium chloride (50 mL) were added to the residue and stirring was continued for 30 min. The organic layer was separated, washed three times with water and dried over anhydrous sodium sulfate. The organic layer was evaporated to dryness under reduced pressure, and the resulting crude product was recrystallized from dichloromethane-ethanol (10:1) to give 8.0 g of white solid in 74.8% yield.HPLC purity was 99.0%. Mass spectrum (ESI) m/z: (M+H)=376.4.

target

VEGFR1/FLT1

storage

Store at -20°C

References

[1]. jenny e. hernandez-davies, joan p. zape, elliot m. landaw, et al. the multitargeted receptor tyrosine kinase inhibitor linifanib (abt-869) induces apoptosis through an akt and glycogen synthase kinase 3β–dependent pathway. mol. cancer ther., 2011, 10(6):949-59.
[2]. joyce e. ohm, michael r. shurin, clemens esche, et al. effect of vascular endothelial growth factor and flt3 ligand on dendritic cell generation in vivo. journal of immunology, 1999, 163:3260-3268.

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