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Pazopanib Hydrochloride

VEGFR/PDGFR/FGFR/c-Kit/ c-Fms inhibitor CAS# 635702-64-6

Pazopanib Hydrochloride

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Chemical structure

Pazopanib Hydrochloride

3D structure

Chemical Properties of Pazopanib Hydrochloride

Cas No. 635702-64-6 SDF Download SDF
PubChem ID 11525740 Appearance Powder
Formula C21H24ClN7O2S M.Wt 473.98
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GW786034
Solubility DMSO : 10 mg/mL (21.10 mM; Need ultrasonic)
Chemical Name 5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide;hydrochloride
SMILES CC1=C(C=C(C=C1)NC2=NC=CC(=N2)N(C)C3=CC4=NN(C(=C4C=C3)C)C)S(=O)(=O)N.Cl
Standard InChIKey MQHIQUBXFFAOMK-UHFFFAOYSA-N
Standard InChI InChI=1S/C21H23N7O2S.ClH/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16;/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25);1H
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Pazopanib Hydrochloride

DescriptionPazopanib (GW786034) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM, respectively.
TargetsVEGFR1VEGFR2VEGFR3PDGFRFGFR  
IC5010 nM30 nM47 nM84 nM74 nM  

Protocol

Kinase Assay [1]
VEGFR enzyme assays are initiated by the addition of 10 μL of activated VEGFR2 kinase solution [final concentration, 1 nM enzyme in 0.1 M 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.5, containing 0.1 mg/mL bovine serum albumin (BSA), 300 μM dithiothreitol (DTT)] to 10 μL substrate solution [final concentration, 360 nM peptide, (biotin-aminohexyl-EEEEYFELVAKKKK-NH2), 75 μM ATP, 10 μM MgCl2], and 1 μL of titrated compound (Pazopanib) in DMSO. Plates are incubated at room temperature for 60 min, and then the reaction is quenched by the addition of 20 μL of 100 mM ethylene diamine tetraacetic acid (EDTA). After quenching, 20 μL HTRF reagents (final concentration, 15 nM Streptavidin-linked allophycocyanin, 1 nM Europium-labeled antiphosphotyrosine antibody diluted in 0.1 mg/mL BSA, 0.1 M HEPES, pH 7.5) is added and the plates incubated for a minimum of 10 min. The fluorescence at 665 nM is measured with a plate reader[1].

Cell Assay [1]
The effect of Pazopanib on cell proliferation is measured using 5-bromo-2-deoxyuridine (BrdU) incorporation method using commercially available kits. HUVEC is seeded in medium containing 5% fetal bovine serum (FBS) in type 1 collagen coated 96-well plates and incubated overnight at 37°C, 5% CO2. The medium is aspirated from the cells, and various concentrations of Pazopanib in serum-free medium are added to each well. After 30 min, either VEGF (10 ng/mL) or bFGF (0.3 ng/mL) is added to the wells. Cells are incubated for an additional 72 h and BrdU (10 μM) is added during the last 18 to 24 h of incubation. At the end of incubation, BrdU incorporation in cells is measured by ELISA. Data are fitted with a curve described by the equation, y=Vmax(1−(x/(K+x))), where K is equal to the IC50[1].

Animal Administration [1][2]
Mice[1] Tumors are initiated by injection of tumor cell suspension in 8−12 week old nude mice. When tumors reach a volume of 100−200 mm3, mice are randomized and divided into groups of eight. Pazopanib is administered once or twice daily at 10, 30, or 100 mg/kg. Animals are euthanized by inhalation of CO2 at the completion of the study. Tumor volume is measured twice weekly by calipers, using the equation: tumor volume (mm3)=(length×width2)/2. Results are routinely reported as % inhibition=1−(average growth of the drug treated population/average growth of vehicle treated control population). Rats[2] Male Brown-Norway (BN; pigmented) rats weighing 200 to 250 g are acclimatized for at least two days prior to any experimental procedure. After overnight fasting for 12-16 h, an intraperitoneal injection of 30 mg/mL solution of Streptozotocin in 10 mM citrate buffer (pH 4.5) is administered (60 mg/kg body weight) to induce diabetes. After 3-4 h of Streptozotocin injection, animals are put on a regular diet and 24 h after Streptozotocin injection, blood sample (5-10 μL) is collected via tail vein. The blood glucose levels in the animals are determined with a glucose monitor. Animals with blood glucose levels greater than 250 mg/dL are considered diabetic. The animals are divided into three groups. Group 1: Healthy (n=12), Group 2: Diabetic (n=12) and Group 3: Diabetic+Treatment (n=12). Treatment is started immediately after diabetes induction. Both eyes are dosed twice daily for 30 days with 0.5 % w/v Pazopanib suspension (10 μL volume in each eye) and animals in all groups are sacrificed on day 31, 16-17 h after last dose on day 30.

References:
[1]. Harris PA, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem. 2008, 51(15), 4632-4640. [2]. Thakur A, et al. Pazopanib, a multitargeted tyrosine kinase inhibitor, reduces diabetic retinal vascular leukostasis and leakage. Microvasc Res. 2011 Nov;82(3):346-50.

Pazopanib Hydrochloride Dilution Calculator

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Pazopanib Hydrochloride Molarity Calculator

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Preparing Stock Solutions of Pazopanib Hydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1098 mL 10.549 mL 21.0979 mL 42.1959 mL 52.7448 mL
5 mM 0.422 mL 2.1098 mL 4.2196 mL 8.4392 mL 10.549 mL
10 mM 0.211 mL 1.0549 mL 2.1098 mL 4.2196 mL 5.2745 mL
50 mM 0.0422 mL 0.211 mL 0.422 mL 0.8439 mL 1.0549 mL
100 mM 0.0211 mL 0.1055 mL 0.211 mL 0.422 mL 0.5274 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Pazopanib Hydrochloride

Pazopanib HCl is a receptor tyrosine kinase inhibitor that targets multiple kinases, including VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit, and c-Fms, with IC50s 10nM, 30nM, 47nM, 84nM, 74nM, 140nM, and 146nM respectively [1-3]. Pazopanib inhibits both tumor growth and angiogenesis through suppressing these targets. In preclinical studies, it has shown anti-tumor activity against several human tumor xenografts, including renal, prostate, colon, lung, melanoma, head and neck, and breast cancer [4]. It also showed desirable pharmacokinetics and oral bioavailability in animal models [4].

Pazopanib has been approved for advanced/metastatic renal cell carcinoma and advanced soft tissue sarcomas by multiple regulatory administrations worldwide, including FDA, EMA, MHRA and TGA. In the clinical trial for soft tissue sarcomas, Pazopanib improved median progression-free survival (PFS) to 4.6 months compared to 1.6 months for patients receiving placebo [5]. In the trial for renal cell carcinoma, Pazopanib increased the median PFS from 4.2 monthe (placebo) to 9.2 months [5]. The most common adverse effect of Pazopanib were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting [6].

References:
1. Verweij J, Sleijfer S. Pazopanib, a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother 2013; 14: 929-935.
2. Pick AM, Nystrom KK. Pazopanib for the treatment of metastatic renal cell carcinoma. Clin Ther 2012; 34: 511-520.
3. Bukowski RM, Yasothan U, Kirkpatrick P. Pazopanib. Nat Rev Drug Discov 2010; 9: 17-18.
4. Sonpavde G, Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 2007; 9: 115-119.
5. http://www.cancer.gov/cancertopics/druginfo/fda-pazopanibhydrochloride
6. http://www.gsksource.com/gskprm/en/US/adirect/gskprm?cmd=ProductDetailPage&product_id=1336067580985&featureKey=603422

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References on Pazopanib Hydrochloride

Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process.[Pubmed:19427156]

J Pharm Biomed Anal. 2009 Sep 8;50(2):144-50.

Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of Pazopanib Hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.

Analytical control of process impurities in Pazopanib hydrochloride by impurity fate mapping.[Pubmed:20189340]

J Pharm Biomed Anal. 2010 Aug 1;52(4):493-507.

Understanding the origin and fate of organic impurities within the manufacturing process along with a good control strategy is an integral part of the quality control of drug substance. Following the underlying principles of quality by design (QbD), a systematic approach to analytical control of process impurities by impurity fate mapping (IFM) has been developed and applied to the investigation and control of impurities in the manufacturing process of Pazopanib Hydrochloride, an anticancer drug approved recently by the U.S. FDA. This approach requires an aggressive chemical and analytical search for potential impurities in the starting materials, intermediates and drug substance, and experimental studies to track their fate through the manufacturing process in order to understand the process capability for rejecting such impurities. Comprehensive IFM can provide elements of control strategies for impurities. This paper highlights the critical roles that analytical sciences play in the IFM process and impurity control. The application of various analytical techniques (HPLC, LC-MS, NMR, etc.) and development of sensitive and selective methods for impurity detection, identification, separation and quantification are highlighted with illustrative examples. As an essential part of the entire control strategy for Pazopanib Hydrochloride, analytical control of impurities with 'meaningful' specifications and the 'right' analytical methods is addressed. In particular, IFM provides scientific justification that can allow for control of process impurities up-stream at the starting materials or intermediates whenever possible.

Characterization of forced degradation products of pazopanib hydrochloride by UHPLC-Q-TOF/MS and in silico toxicity prediction.[Pubmed:26349647]

J Mass Spectrom. 2015 Jul;50(7):918-28.

Pazopanib (PZ), an anti-cancer drug, was subjected to forced degradation under hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress conditions as per International Conference on Harmonization guidelines. A selective stability indicating validated method was developed using a Waters Acquity UPLC HSS T3 (100 x 2.1 mm, 1.7 microm) column in gradient mode with ammonium acetate buffer (10 mM, pH 5.0) and acetonitrile. PZ was found to degrade only in photolytic conditions to produce six transformation products (TPs). All the TPs were identified and characterized by liquid chromatography/atmospheric pressure chemical ionization-quadrupole-time of flight mass spectrometry experiments in combination with accurate mass measurements. Plausible mechanisms have been proposed for the formation of TPs. In silico toxicity was predicted using TOPKAT and DEREK softwares for all the TPs. The TP, N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methylpyrimidine-2,4-diamine, was found to be genotoxic, whereas all other TPs with sulfonamide moiety were hepatotoxic. The data reported here are expected to be of significance as this study foresees the formation of one potential genotoxic and five hepatotoxic degradation/transformation products.

Description

Pazopanib Hydrochloride (GW786034 Hydrochloride) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ, c-Kit, FGFR1, and c-Fms with an IC50 of 10, 30, 47, 84, 74, 140 and 146 nM, respectively.

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