KRN 633 Chemical Properties

Melting point:

231-232°C

Boiling point:

545.6±50.0 °C(Predicted)

Density 

1.321

storage temp. 

-20°C

solubility 

DMSO: soluble3mg/mL, clear (warmed)

pka

13.08±0.70(Predicted)

form 

powder

color 

white to beige

Safety Information

Hazard Codes 

Xn

Risk Statements 

22

WGK Germany 

3

KRN 633 Usage And Synthesis

Uses

KRN 633 is an ATP-competitive inhibitor of VEGFR1/2/3 with IC50 of 170 nM/160 nM/125 nM and also inhibits PDGFRα/β with IC50 of 965 nM/9850 nM.

Uses

KRN 633 is an ATP-competitive inhibitor of vascular endothlial growth factor receptor tyrosine kinase (VEGFR). KRN 633 also suppresses VEGF-dependent activation of MAPK and cell proliferation and demonstrates antitumor and antiangiogenic activity by inhibiting vessel formation and vascular permeability in human tumor xenograft models.

Biological Activity

krn 633 is a selective inhibitor of vegfr-1, vegfr-2 and vegfr-3 with ic50 value of 170 nm, 160 nm and 125 nm [1].vascular endothelial growth factor receptor (vegfr) is a protein and plays an important role in tumor angiogenesis by cooperating with its ligand vegf [1].krn 633 is a potent vegfr inhibitor. when tested with huvecs, krn 633 inhibited the cell proliferation that mediated by vegf with the ic50 value of 14.9 nmol/l and suppressed the capillary tube formation by ~50% at the dose of 10 nmol/l [1].in mid-pregnant mice model, krn633 was used at the dose of 5 mg/kg once daily from embryonic day 13.5 until the day of delivery and the effect on vascular growth was slightly delayed on postnatal day 4 (p4) and on p8 it was observed that krn633 resulted in the decreased numbers of central arteries and veins and abnormal branching of the central arteries [2]. when tested with athymic mouse xenograft ht29 cells model, administration of krn633 inhibited tumor growth as ~90% from the initial tumor volume rangs from 500-667 mm3, while had less effect du145 xenograft mouse models by inhibiting tumor angiogenesis and vascular permeability [1].

Biochem/physiol Actions

KRN633 is a cell-permeable; reversible and ATP-competitive inhibitor of vascular endothelial growth factor receptor tyrosine kinase (VEGFR) with IC50 values of 170, 160, and 125 nM for VEGFR-1, -2, -3, respectively. Krn633 inhibits PDGFR-α and c-Kit only at higher concentrations (IC50 = 0.97 and 4.33 μM, respectively) and is inactive towards a panel of 17 other kinases (IC50 >/= 10 μM).

Synthesis

Example 62 N-[2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl]-N'-propylurea was synthesized as follows: 2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (5.13 g) was dissolved in a solvent mixture of chloroform (100 mL) and triethylamine (50 mL). Subsequently, a solution of chloroform (3 mL) of triphosgene (4.59 g) was slowly added to this solution. The reaction mixture was stirred at room temperature for 30 minutes. Next, n-propylamine (2.74 g) was added to the reaction system and stirring was continued for 2 hours. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction solution for neutralization, followed by extraction with chloroform. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography with chloroform/methanol (50:1, v/v) as eluent to afford the target product N-[2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl]-N'-propylurea in 4.14 g in 64% yield. The structure of the product was confirmed by 1H-NMR (DMSO-d6, 400 MHz) and mass spectrometry (ESI-MS).1H-NMR data: δ 0.91 (t, J = 7.3 Hz, 3H), 1.41-1.53 (m, 2H), 3.05-3.12 (m, 2H), 3.97 (s, 3H), 3.99 (s, 3H). 6.99 (t, J = 5.4 Hz, 1H), 7.22 (dd, J = 2.7 Hz, 9.0 Hz, 1H), 7.38 (s, 1H), 7.46 (d, J = 2.9 Hz, 1H), 7.54 (s, 1H), 8.04 (s, 1H), 8.20 (d, J = 9.3 Hz, 1H), 8.55 (s, 1H). Mass spectral data: m/z 417 (M++1).

in vivo

target

VEGFR3

IC 50

VEGFR1: 170 nM (IC₅₀); VEGFR2: 160 nM (IC₅₀); VEGFR3: 125 nM (IC₅₀)

References

[1]. nakamura, k., et al., krn633: a selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth. mol cancer ther, 2004. 3(12): p. 1639-49.
[2]. morita, a., et al., treatment of mid-pregnant mice with krn633, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, induces abnormal retinal vascular patterning in their newborn pups. birth defects res b dev reprod toxicol, 2014. 101(4): p. 293-9.

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