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AMG-458
本产品不向个人销售，仅用作科学研究，不用于任何人体实验及非科研性质的动物实验。
AMG-458图片
CAS NO:913376-83-7
规格:≥98%
包装与价格：
包装价格(元)
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW)539.58
FormulaC30H29N5O5
CAS No.913376-83-7
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: 21 mg/mL (38.9 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)15% Captisol+citrate vehicle: 30 mg/mL
SynonymsAMG-458; AMG 458; AMG458;

Chemical Name: 1-(2-hydroxy-2-methylpropyl)-N-(5-((7-methoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

InChi Key: GLBZSOQDAOLMGC-UHFFFAOYSA-N

InChi Code: InChI=1S/C30H29N5O5/c1-19-27(29(37)35(20-8-6-5-7-9-20)34(19)18-30(2,3)38)28(36)33-26-13-11-22(17-32-26)40-25-14-15-31-24-16-21(39-4)10-12-23(24)25/h5-17,38H,18H2,1-4H3,(H,32,33,36)

SMILES Code: O=C(C1=C(C)N(CC(C)(O)C)N(C2=CC=CC=C2)C1=O)NC3=NC=C(OC4=CC=NC5=CC(OC)=CC=C45)C=C3

实验参考方法
In Vitro

In vitro activity: AMG 458 also inhibits HGF-mediated c-Met phosphorylation in PC3 and CT26 cells with IC50 of 60 and 120 nM. AMG 458 is observed to bind covalently to liver microsomal proteins from rats and humans in the absence of NADPH. AMG 458 is believed to react with thiol groups in proteins, producing a methoxy quinoline thioether conjugate. A recent study shows that the constitutive phosphorylation of c-Met in H441 is abrogated by AMG 458. The basal and HGF-induced phosphorylation of c-Met in A549 is attenuated by AMG 458. The combination of radiation therapy and AMG 458 treatment is found to synergistically increase apoptosis in the H441 cell line by reduction of p-Akt and p-Erk levels, but not in A549.

Kinase Assay: AMG 458 is a potent c-Met inhibitor with Ki of 1 nM ~ 2.0 nM. AMG-458 was found to significantly inhibit tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.

Cell Assay: AMG 458 also inhibits HGF-mediated c-Met phosphorylation in PC3 and CT26 cells with IC50 of 60 and 120 nM.

In VivoAMG 458 is metabolically stable in the liver microsomes of mouse, rat, dog, monkey, and human with low intrinsic clearances (Clint:<5, 62, 8, 8, 18 (μL/min)/mg, respectively). When administered orally, AMG 458 achieves remarkably high bioavailability in all species tested. Oral dosing of AMG 458 inhibits HGF-mediated c-Met phosphorylation with an approximate ED90 of 30 mg/kg and an associated plasma exposure of approximately 15 μM at 6 hours. AMG 458 significantly inhibits tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models at 30 and 100 mg/kg q.d. and 30 mg/kg b.i.d.with no adverse effect on body weight. High concentrations of AMG 458 in some organs may produce toxicity via oxidative stress.
Animal modelFemale CD-1 nu/nu mice aged 6-8) bearing NIH3T3/TPR-Met and U-87 MG xenograft model
Formulation & DosageFormulated in 20% Captisol with pH adjusted to 3.5 using methanesulfonic acid (i.v. injection); Formulated in 2% HPMC and 1% Tween-80 with pH adjusted to 2.2 using HCl (p.o.); 10, 30, 100 mg/kg; i.v. or p.o.
ReferencesJ Med Chem. 2008 Jul 10;51(13):3688-91; Chem Res Toxicol. 2008 Nov;21(11):2216-22.