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| 25mg |
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Purity: ≥98%
Vatalanib ((PTK787 or ZK 222584, cpg-79787) is a novel, potent and orally bioavailable inhibitor of VEGFR2/KDR with IC50 of 37 nM in a cell-free assay, it is less potent against VEGFR1/Flt-1, and is 18-fold against VEGFR3/Flt-4. It is an analog of anilinophthalazine that may have antitumor properties. Vatalanib binds to VEGFR 1 and 2's protein kinase domain, inhibiting it. Additionally, this substance binds to and inhibits c-Kit, c-Fms, and the PDGF receptor, among other related receptor tyrosine kinases.
| Targets |
VEGFR2/KDR (IC50 = 37 nM); VEGFR1/FLT1 (IC50 = 77 nM); VEGFR2/Flk1 (IC50 = 270 nM); PDGFRβ (IC50 = 580 nM); VEGFR3/FLT4 (IC50 = 660 nM)
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| ln Vitro |
Vatalanib also inhibits PDGFRβ, Flk, and c-Kit with IC50 values of 580 nM, 730 nM, and 270 nM, respectively. At an IC50 of 7.1 nM, vatalanib inhibits the thymidine incorporation that VEGF induces in HUVECs. It also suppresses VEGF-induced migration and survival of endothelial cells in the same dose range in a dose-dependent manner, without having an adverse effect on cells that do not express VEGF receptors[1]. According to a new study, vatalanib increases the levels of the protein Bax and decreases Bcl-xL and Bcl-2, which significantly inhibits the growth of hepatocellular carcinoma cells and enhances the IFN/5-FU-induced apoptosis[2].
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| ln Vivo |
Vatalanib results in dose-dependent suppression of the angiogenic response to VEGF and PDGF following a single oral dosage (25–100 mg/kg) in two models: one using growth factor implants, the other using tumor cell-driven angiogenesis. Vatalanib also inhibits the growth and metastases of multiple human carcinomas in nude mice within the same dose range, while having no discernible effect on bone marrow leukocytes or circulating blood cells[1].
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| Enzyme Assay |
Every GST-fused kinase is cultured in buffer conditions that are optimized. ATP in a 30 μL total volume for 10 minutes at room temperature, either with or without the test drug vatalanib. To stop the reaction, add 10 μL of 250 mM EDTA[1].
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| Cell Assay |
In 96-well plates coated with 1.5% gelatin, subconfluent HUVECs are seeded. A constant concentration of either VEGF (50 ng/mL), bFGF (0.5 ng/mL), or FCS (5%), with or without vatalanib, is added to the basal medium after 24 hours, replacing the growth medium. Additionally included as a control are wells devoid of growth factor. Cells are incubated for a further 24 hours after the addition of the BrdUrd labeling solution, and then they are fixed, blocked, and have peroxidase-labeled anti-BrdUrd antibody added. The 3,3',5,5'-tetramethylbenzidine substrate is then used to detect the bound antibody[1].
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| Animal Protocol |
On the dorsal flank of C57/C6 mice, a 0.5 mL porous Teflon chamber containing 0.8% w/v agar, 0.2% heparin (20 units/mL), growth factors (3 g/mL human VEGF, 2 g/mL human PDGF), or neither, is implanted s.c. Beginning one day prior to chamber implantation and continuing for five days thereafter, the mice are treated with either vehicle (water) or Vatalanib (12.5, 25 or 50 mg/kg dihydrochloride p.o. once daily). The treatment concludes with the mice's death and the removal of the chambers. Measurements of the tissue's hemoglobin content are used to determine the amount of blood present after the vascularized tissue surrounding the chamber is carefully removed and weighed[1].
To evaluate the effect on tumor proliferation, Vatalanib (PTK-787; ZK-222584; CGP-79787) was administered to nude mice with established SCLC micrometastases. The drug was dissolved in polyethylene glycol 400. It was administered via intraperitoneal (i.p.) injections at a dose of 50 mg/kg, twice daily. The treatment regimen began one day prior to the RFA procedure and continued until the mice were sacrificed at day 1, 7, or 14 following RFA [3]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Absorption is rapid. Metabolism/Metabolites Metabolism is primarily through oxidation. Two pharmacologically inactive metabolites, CGP 84368/ZK 260120 and NVP AAW378/ZK 261557, have systemic exposures comparable to vataranilide and are the major contributors to total systemic exposure. Biological Half-Life Approximately 6 hours. |
| References |
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| Additional Infomation |
Vatalanib belongs to the phthalazine class of compounds. Its structure consists of hydrogen atoms at positions 1 and 4 of the phthalazine molecule replaced by p-chlorophenylamino and pyridin-4-ylmethyl, respectively. It is a multi-target tyrosine kinase inhibitor that inhibits all VEGFR, PDGFR, and c-Kit subtypes. Vatalanib possesses multiple functions, including antitumor activity, EC 2.7.10.1 (receptor protein tyrosine kinase) inhibition, angiogenesis inhibition, and vascular endothelial growth factor receptor antagonism. It belongs to the phthalazine, pyridine, monochlorobenzene, and secondary amine classes of compounds. Vatalanib (PTK787/ZK-222584) is a novel oral anti-angiogenic molecule that inhibits all known vascular endothelial growth factor receptors. Vatalanib is being investigated for the treatment of solid tumors. Vatalanib is an orally bioavailable aniline phthalazine drug with potential antitumor activity. Vatalanib binds to and inhibits the activity of the protein kinase domains of vascular endothelial growth factor receptors 1 and 2; both of these receptor tyrosine kinases are involved in angiogenesis. The drug also binds to and inhibits related receptor tyrosine kinases, including platelet-derived growth factor (PDGF) receptors, c-Kit, and c-Fms.
See also: Vatalanib succinate (note moved to). Indications In combination with first-line and second-line chemotherapy for the treatment of metastatic colorectal cancer and non-small cell lung cancer (NSCLC). Mechanism of Action Valtalanib potently inhibits vascular endothelial growth factor (VEGF) receptor tyrosine kinases, enzymes that play a crucial role in angiogenesis, which contributes to tumor growth and metastasis. Pharmacodynamics Valtalanib is a novel oral angiogenesis inhibitor developed by Schering (in collaboration with Novartis). Vatalanib selectively inhibits the tyrosine kinase domains of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor (PDGF) receptor, and c-KIT. |
| Molecular Formula |
C20H15CLN4
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|---|---|
| Molecular Weight |
346.8129
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| Exact Mass |
346.098
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| Elemental Analysis |
C, 69.26; H, 4.36; Cl, 10.22; N, 16.15
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| CAS # |
212141-54-3
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| Related CAS # |
Vatalanib dihydrochloride;212141-51-0;Vatalanib succinate;212142-18-2
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| PubChem CID |
151194
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| Appearance |
White to off-white crystalline powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
587.8±50.0 °C at 760 mmHg
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| Melting Point |
209-212ºC
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| Flash Point |
309.3±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.711
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
25
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| Complexity |
407
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C([H])C(=C([H])C=1[H])N([H])C1C2=C([H])C([H])=C([H])C([H])=C2C(C([H])([H])C2C([H])=C([H])N=C([H])C=2[H])=NN=1
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| InChi Key |
YCOYDOIWSSHVCK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H15ClN4/c21-15-5-7-16(8-6-15)23-20-18-4-2-1-3-17(18)19(24-25-20)13-14-9-11-22-12-10-14/h1-12H,13H2,(H,23,25)
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| Chemical Name |
N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine
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| Synonyms |
PTK787/ZK 222584; CGP-7978; PTK787; PTK 787; PTK-787; ZK 222584; ZK222584; ZK-222584; CGP79787D; CGP 79787; CGP-797870; ZK-232934
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 21.3~100 mg/mL (50.6~360.4 mM)
Ethanol: ~6 mg/mL (~14.3 mM) Water: ~10 mg/mL (~23.8 mM) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8834 mL | 14.4171 mL | 28.8342 mL | |
| 5 mM | 0.5767 mL | 2.8834 mL | 5.7668 mL | |
| 10 mM | 0.2883 mL | 1.4417 mL | 2.8834 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00072475 | Completed | Drug: vatalanib | Myelodysplastic Syndromes Leukemia |
Alliance for Clinical Trials in Oncology |
December 2003 | Phase 2 |
| NCT00268918 | Completed | Drug: PTK787 Drug: Docetaxel |
Ovarian Cancer Cervical Cancer |
Dana-Farber Cancer Institute | September 2005 | Phase 1 |
| NCT00117299 | Completed | Drug: PTK787/ZK222584 | Sarcoma | University of Helsinki | September 2004 | Phase 2 |
| NCT00056459 | Completed | Drug: Vatalanib | Colorectal Neoplasms Rectal Neoplasms |
Novartis | February 2003 | Phase 3 |
| NCT00056446 | Completed | Drug: Vatalanib | Colorectal Neoplasms Colonic Neoplasms |
Novartis Pharmaceuticals | January 2003 | Phase 3 |
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