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3-[(quinolin-4-ylmethyl)amino]-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide

ChemBase编号:72577
分子式:C22H16F3N3O2S
平均质量:443.4415496
单一同位素质量:443.09153243
SMILES和InChIs

SMILES:
c1ccc2c(c1)c(ccn2)CNc1c(scc1)C(=O)Nc1ccc(cc1)OC(F)(F)F
Canonical SMILES:
O=C(c1sccc1NCc1ccnc2c1cccc2)Nc1ccc(cc1)OC(F)(F)F
InChI:
InChI=1S/C22H16F3N3O2S/c23-22(24,25)30-16-7-5-15(6-8-16)28-21(29)20-19(10-12-31-20)27-13-14-9-11-26-18-4-2-1-3-17(14)18/h1-12,27H,13H2,(H,28,29)
InChIKey:
FGTCROZDHDSNIO-UHFFFAOYSA-N

引用这个纪录

CBID:72577 http://www.chembase.cn/molecule-72577.html

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名称和登记号

名称和登记号

名称 登记号
IUPAC标准名
3-[(quinolin-4-ylmethyl)amino]-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide
IUPAC传统名
3-[(quinolin-4-ylmethyl)amino]-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide
别名
OSI-930
CAS号
728033-96-3
PubChem SID
162037502
PubChem CID
9868037

数据来源

数据来源

所有数据来源 商品来源 非商品来源
数据来源 数据ID 价格
Selleck Chemicals
S1220 external link 加入购物车 请登录
数据来源 数据ID
PubChem 9868037 external link

理论计算性质

理论计算性质

JChem
Acid pKa 11.211401  质子受体
质子供体 LogD (pH = 5.5) 6.382368 
LogD (pH = 7.4) 6.413551  Log P 6.4140296 
摩尔折射率 110.2794 cm3 极化性 42.465202 Å3
极化表面积 63.25 Å2 可自由旋转的化学键
里宾斯基五规则 false 

分子性质

分子性质

理化性质 安全信息 药理学性质 产品相关信息 生物活性(PubChem)
溶解度
DMSO expand 查看数据来源
保存条件
-20°C expand 查看数据来源
作用靶点
c-Kit expand 查看数据来源
VEGFR expand 查看数据来源
成盐信息
Free Base expand 查看数据来源

详细说明

详细说明

Selleck Chemicals Selleck Chemicals
Selleck Chemicals -  S1220 external link
Research Area
Description Solid tumours
Biological Activity
Description OSI-930 is a potent inhibitor of Kit, KDR, Flt, CSF-1R, c-Raf and Lck with IC50 of 80 nM, 9 nM, 8 nM, 15 nM, 41 nM and 22 nM, respectively.
Targets Kit (activated) KDR Flt1 CSF-1R c-Raf Lck
IC50 80 nM 9 nM 8 nM 15 nM 41 nM 22 nM [1]
In Vitro OSI-930 inhibits the cell proliferation in the HMC-1 cell line with IC50 of 14 nM without significant effect on growth of the COLO-205 cell line that does not express a constitutively active mutant receptor tyrosine kinase. Moreover, OSI-930 also induces apoptosis in HMC-1 cell line with EC50 of 34 nM. [1] A recent study shows that OSI-930 inactivates purified, recombinant cytochrome P450 (P450) 3A4 with a Ki of 24 μM in a time- and concentration-dependent mode. [2]
In Vivo OSI-930, administrated at the maximally efficacious dose of 200 mg/kg by oral gavage, exhibits potent antitumor activity in a broad range of preclinical xenograft models including HMC-1, NCI-SNU-5, COLO-205 and U251 xenograft models. [1]
Clinical Trials OSI-930 is currently in Phase I clinical trials in patients with Advanced Solid Tumors.
Features
Combination Therapy
Description Combination of OSI-930 and Erlotinib is currently in Phase I clinical trials in patients with Advanced Solid Tumors.
Protocol
Kinase Assay [1]
Protein kinase assays Protein kinase assays are either done in-house by ELISA-based assay methods (Kit, KDR, PDGFRα, and PDGFRβ) or by a radiometric method. In-house ELISA assays used poly(Glu:Tyr) as the substrate bound to the surface of 96-well assay plates; phosphorylation is then detected using an antiphosphotyrosine antibody conjugated to HRP. The bound antibody is then quantitated using ABTS as the peroxidase substrate by measuring the absorbance at 405/490 nm. All assays uses purified recombinant kinase catalytic domains that are either expressed in insect cells or in bacteria. The Kit and EGFR protein used for in-house assays are prepared internally; other enzymes are obtained. Recombinant Kit protein is expressed as an NH2-terminal glutathione S-transferase fusion protein in insect cells and is initially purified as a nonphosphorylated (nonactivated) enzyme with a relatively high Km for ATP (400 μM). In some assays, an activated (tyrosine phosphorylated) form of the enzyme is prepared by incubation with 1 mM ATP for 1 hour at 30 °C. The phosphorylated protein is then passed through a desalting column to remove the majority of the ATP and stored at ?80 °C in buffer containing 50% glycerol. The resultant preparation has a considerably higher specific activity and a lower Km for ATP (25 μM) than the initial nonphosphorylated preparation. The inhibition of Kit autophosphorylation by OSI-930 is assayed by incubation of the nonphosphorylated enzyme at 30 °C in the presence of 200 μM ATP and various concentrations of OSI-930. The reaction is stopped by removal of aliquots into SDS-PAGE sample buffer followed by heating to 100 °C for 5 minutes. The degree of phosphorylation of Kit is then determined by immunoblotting for both total Kit and phosphorylated Kit.
Cell Assay [1]
Cell Lines HMC-1 and COLO-205
Concentrations 0--1 μM
Incubation Time 48 hours
Methods For assays of cell proliferation and apoptosis, cells are seeded into 96-well plates and incubated for 2 to 3 days in the presence of OSI-930 at various concentrations. Inhibition of cell growth is determined by luminescent quantitation of the intracellular ATP content using CellTiterGlo. Induction of caspase-dependent apoptosis by OSI-930 is quantitated by an enzymatic caspase 3/7 assay. Inhibition of angiogenesis by OSI-930 is monitored using the rat aortic ring endothelial sprout outgrowth assay. Sections of aorta are prepared from CO2-euthanized male rats and cultured in vitro in a collagen matrix in the presence or absence of OSI-930. The collagen matrix is prepared from type 1 rat tail collagen solubilized in 0.1% acetic acid at 3 mg/mL, which is combined with 0.125 volume collagen buffer (0.05 N NaOH, 200 mM HEPES, 260 mM NaHCO3), 0.125 volume of medium 199, 0.0125 volume of 1 M NaOH, and 1% GlutaMax. Aortic rings are embedded in 0.4 mL of this matrix in six-well plates, to which 0.5 mL endothelial basal medium and the appropriate amount of OSI-930 is added; the rings are then incubated for 10 days and the resultant angiogenic sprout outgrowth is digitally quantitated from images by measurement of the sprout-containing area within a series of concentric rings around the aortic tissue area.
Animal Study [1]
Animal Models HMC-1, NCI-SNU-5, COLO-205 and U251 cells are injected s.c. into the right flank of CD1 nu/nu mice.
Formulation OSI-930 is dissolved in either Labrafil M 1944 CS or polyethylene glycol (PEG)-400/water (50:50).
Doses ≤200 mg/kg
Administration Administered via p.o.
References
[1] Garton AJ, et al. Cancer Res. 2006, 66(2):1015-1024.
[2] Lin HL, et al. Drug Metab Dispos. 2011, 39(2), 345-350.

参考文献

参考文献

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专利

专利

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