Flumatinib - CAS 895519-90-1
Catalog number: B0084-474894
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C29H29F3N8O
Molecular Weight:
562.59
COA:
Inquire
Targets:
c-Kit | VEGFR
Description:
Flumatinib is a multi-kinase inhibitor of c-Abl, PDGFRβ and c-Kit with IC50 values of 1.2 nM, 307.6 nM and 2662 nM respectively. It can predominantly inhibit the autophosphorylation of Bcr-Abl in K562 cell in vitro. It can inhibit the phosphorylation of c-Kit in Mo7e cell and the phosphorylation of PDGFR in Swiss3T3 cell in higher concentration. It has no or little effect on other tyrosine kinase including EGFR、KDR、c-Src andHER2. It can reduce the expression of C-MYC, HIF-1 α and VEGF in U266 cell line in a time- and dose-dependent manners. It effectively overcame the drug resistance of certain KIT mutants with activation loop mutations. It was developed by Jiangsu Hansoh Pharmaceutical Co., Ltd. and is currently in Phase III clinical trials in China for the treatment of chronic myelogenous leukemia (CML).
Purity:
>98%
Appearance:
Solid powder
Synonyms:
BenzaMide, 4-[(4-Methyl-1-piperazinyl)Methyl]-N-[6-Methyl-5-[[4-(3-pyridinyl)-2-pyriMidinyl]aMino]-3-pyridinyl]-3-(trifluoroMethyl)-;4-[(4-Methyl-1-piperazinyl)methyl]-N-[6-methyl-5-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-3-pyridinyl]-3-(trifluoromethyl)benzamide
Solubility:
DMSO: ≥ 32 mg/mL
Storage:
-20°C Freezer
MSDS:
Inquire
Application:
Flumatinib is used for the treatment of chronic myelogenous leukemia (CML).
Quality Standard:
In-house standard
Shelf Life:
2 month in rt, long time
Quantity:
Milligrams-Grams
Density:
1.340±0.06 g/cm3 | Condition: Temp: 20 °C Press: 760 Torr
InChIKey:
BJCJYEYYYGBROF-UHFFFAOYSA-N
InChI:
InChI=1S/C29H29F3N8O/c1-19-26(38-28-34-9-7-25(37-28)21-4-3-8-33-16-21)15-23(17-35-19)36-27(41)20-5-6-22(24(14-20)29(30,31)32)18-40-12-10-39(2)11-13-40/h3-9,14-17H,10-13,18H2,1-2H3,(H,36,41)(H,34,37,38)
Canonical SMILES:
CC1=C(C=C(C=N1)NC(=O)C2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)NC4=NC=CC(=N4)C5=CN=CC=C5
Current Developer:
Flumatinib was developed by Jiangsu Hansoh Pharmaceutical Co., Ltd. and is currently in Phase III clinical trials.
1.[Metabolic research of domestically developed small molecule tyrosine kinase inhibitors].
Jiang JF;Chen XY;Zhong DF Yao Xue Xue Bao. 2016 Feb;51(2):248-56.
Drug metabolism research plays an essential role in drug discovery and development. Great efforts have been made domestically to be line with the international standardized research on drug metabolism. In this article, we will review new-generation of tyrosine kinase inhibitors(TKIs), these TKIs include icotinib, apatinib, famitinib, flumatinb, allitinib, fruquintinib, and selatinib, among which icotinib and apatinib have been approved by China food and drug administration(CFDA) to reach the market, while others are in clinical trials. For these TKIs, the structural modified sites are active metabolic centers and CYP3A4 is identified as the primary metabolic enzyme. Considering the active intermediates, the crown ether ring of icotinib is oxidated to open to form an aldehyde; the indolylidene ring of famitinib is oxidated followed by rearrangement to form a quinone- imine; the α, β-unsaturated carbonyl group of allitinib is oxidated to form an epoxide, these intermediates are capable of covalently binding biomolecules and generating toxicity. In addition, human (14)C radioactive trials of most of these TKIs have not been conducted, and the data of drug-drug interactions in clinic are also absent, which indicate our deficiency compared to the international regular approaches in metabolic research.
2.Metabolism of flumatinib, a novel antineoplastic tyrosine kinase inhibitor, in chronic myelogenous leukemia patients.
Gong A;Chen X;Deng P;Zhong D Drug Metab Dispos. 2010 Aug;38(8):1328-40. doi: 10.1124/dmd.110.032326. Epub 2010 May 17.
4-(4-Methyl-piperazin-1-ylmethyl)-N-[6-methyl-5-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pyridin-3-yl]-3-trifluoromethyl-benzamide (flumatinib, HH-GV678), an antineoplastic tyrosine kinase inhibitor, is currently in Phase I clinical trials in China for the treatment of chronic myelogenous leukemia (CML). The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways of flumatinib in humans after oral administration. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 34 metabolites; 7 primary metabolites were confirmed by comparison with synthetic reference standards. The results show that the parent drug flumatinib was the main form recovered in human plasma, urine, and feces. The main metabolites of flumatinib in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis. In addition to these phase I metabolites, several phase II glucuronidation and acetylation products were detected in plasma, urine, and feces. The observed circulating metabolites included an N-demethylated metabolite (M1), two hydrolytic metabolites (M3, M4), oxidation metabolites (M2-1, M2-4, M2-7, M2-9, and M14), a glucuronide conjugate (M16-2), and several multiple metabolic products.
3.Simultaneous determination of flumatinib and its two major metabolites in plasma of chronic myelogenous leukemia patients by liquid chromatography-tandem mass spectrometry.
Yang Y;Liu K;Zhong D;Chen X J Chromatogr B Analyt Technol Biomed Life Sci. 2012 May 1;895-896:25-30. doi: 10.1016/j.jchromb.2012.03.008. Epub 2012 Mar 15.
Flumatinib is an antineoplastic tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia (CML). Its major metabolites in the circulation are N-desmethyl flumatinib (M1) and amide hydrolysis product (M3). To investigate the pharmacokinetics of flumatinib in CML patients, a simple, specific and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of flumatinib and its two major metabolites in patient plasma. After a simple, one-step protein precipitation with methanol, flumatinib, its two metabolites, and internal standard (HHGV-E) were separated on a C(18) column using an isocratic mobile phase of methanol:5mM ammonium acetate:formic acid (60:40:0.4, v/v/v). A total chromatographic run time of 4.2 min was achieved. The detection was performed in multiple reaction monitoring mode, using the transitions of m/z 563→m/z 463 for flumatinib, m/z 549→m/z 463 for M1, m/z 303→m/z 175 for M3, and m/z 529→m/z 429 for HHGV-E. The method was linear over the concentration ranges of 0.400-400 ng/mL for flumatinib, 0.100-100 ng/mL for M1, and 0.200-200 ng/mL for M3, using only 50 μL of plasma. The intra- and inter-day precisions were less than 8.
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