796967-16-3

Usage

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].

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.

InChI:InChI=1/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)

Upstream product

• 214360-73-3 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)aniline 
• 796967-18-5 N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]urea 
• 20925-60-4 3-amino-4-chloro-1H-indazole 
• 1145835-80-8 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea monohydrate 
• 452-84-6 3-amino-4-fluorotoluene 
• 599191-73-8 4-iodine-1H-indazol-3-ylamine 
• 79544-29-9 2-fluoro-6-iodobenzonitrile 

Downstream Products

• 1145835-80-8 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea monohydrate 

Relevant academic research and scientific papers

N - (4 - (3 - amino - 1 H - indazole - 4 - yl) phenyl) - N' - (2 - fluoro - 5 - methylphenyl) urea intermediate preparation method

The invention provides a preparation method of N-(4-(3-amino-1H-indazol-4-yl) phenyl)-N'-(2-fluoro-5-methylphenyl) urea and an intermediate thereof. Specifically, the invention provides a preparation method of a borate ester compound as shown in a formula I, and the preparation method comprises the following steps: enabling a compound as shown in a formula III to react with a compound as shown in a formula IV to generate a compound as shown in a formula V, and enabling the compound as shown in the formula V to react with a boron reagent to generate the compound as shown in the formula I. The method has the characteristics of convenience in reaction, easiness in obtainment of the intermediate, high yield, high product purity of above 98.5%, low cost of raw materials and the like, and is suitable for industrial application.

Linifanib-a multi-targeted receptor tyrosine kinase inhibitor and a low molecular weight gelator

In this study we demonstrate that linifanib, a multi-targeted receptor tyrosine kinase inhibitor, with a key urea containing pharmacophore, self-assembles into a hydrogel in the presence of low amounts of solvent. We demonstrate the role of the urea functional group and that of fluorine substitution on the adjacent aromatic ring in promoting self-assembly. We have also shown that linifanib has superior mechanical strength to two structurally related analogues and hence increased potential for localisation at an injection site for drug delivery applications. This journal is

CRYSTALLINE CHEMOTHERAPEUTIC

N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea Crystalline Form 2, ways to make it, formulations comprising it and made with it and methods of treating patients having disease using it are disclosed.

CRYSTALLINE CHEMOTHERAPEUTIC

N-[4-(3-Amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea Crystalline Form 1, ways to make it, formulations comprising it and made with it and methods of treating patients having disease using it are disclosed.

The discovery and development of a safe, practical synthesis of ABT-869

The discovery, development and implementation of two chemical routes to ABT-869 is reported. Optimization of the first-generation heterocycle formation and Suzuki coupling is briefly described. Key features of the second-generation synthesis include the development of a safe hydrazine condensation by utilizing an inorganic base to increase the onset temperature of exothermic decomposition. The second-generation Suzuki reaction is discussed in detail, culminating in the use of an oxygen monitor as a PAT to maximize reproducibility on scale.

Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5- methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor

In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N′-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.