| Identification | Back Directory | [Name]
AMG 458 | [CAS]
913376-83-7 | [Synonyms]
CS-530
AMG 458
AMG 458 USP/EP/BP
1-(2-Hydroxy-2-methylpropyl)-N-[5-[(7-methoxyquinolin-4-yl)oxy]pyridin-2-yl]-5-methyl-3-oxo-2-
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
1H-Pyrazole-4-carboxamide, 2,3-dihydro-1-(2-hydroxy-2-methylpropyl)-N-[5-[(7-methoxy-4-quinolinyl)oxy]-2-pyridinyl]-5-methyl-3-oxo-2-phenyl- | [Molecular Formula]
C30H29N5O5 | [MDL Number]
MFCD17169989 | [MOL File]
913376-83-7.mol | [Molecular Weight]
539.582 |
| Hazard Information | Back Directory | [Uses]
AMG-458 is a potent inhibitor of c-Met with an IC50 of 60 nM. | [Biological Activity]
amg-458 is a potent and selective inhibitor of human and mouse c-met with ic50 value of 1.2 nm and 2.0 nm respectively.c-met, also known as hepatocyte growth factor receptor, is a receptor tyrosine kinase that can be activated by hepatocyte growth factor/scatter factor (hgf/sf). it is a membrane protein which plays an essential role in embryonic development and wound healing.recent study investigated the effect of amg-456 treatment on cell radiosensitizing response. the results showed that amg-458 treatment enhanced radiosensitivity in h441 with higher levels of c-met but not in a549 with lower expression of c-met [1].this component was also used in an animal model to study the role of c-met in the development of tumor. for instance, orally administration of amg-456 resulted in significant inhibition of tumor growth in /tpr-met and u-87 mg xenograft models without any adverse effect on body weight [2]. | [Enzyme inhibitor]
This potent c-Met protein kinase inhibitor (FW = 539.58 g/mol; CAS
913376-83-7; Solubility: 21 mg/mL DMSO; ~1 mg/mL H2O), also named
1- (2-hydroxy-2-methylpropyl) -N- (5- (7-methoxyquinolin-4-yloxy) pyridin-
2-yl) -5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide,
targets the MET proto-oncogene product c-Met, which is the hepatocyte
growth factor receptor possessing tyrosine-kinase activity. The primary
single-chain precursor protein is posttranslationally cleaved to produce the
a and b subunits that are disulfide linked to form the mature receptor.
Various mutations in the MET gene are associated with papillary renal
carcinoma. AMG-458 preferentially inhibits c-Met (Ki = 1.2 nM), showing
~350-fold greater potency than VEGFR2 in cells. AMG-458
significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87
MG xenograft models with no adverse effect on body weight. AMG
458 binds covalently to liver microsomal proteins from rats and humans,
even in the absence of NADPH. When [14C]AMG-458 is incubated with
liver microsomes in the presence of glutathione or N-acetyl cysteine,
quinolone-type thioether adducts can be detected by radiochromatography
and LC/MS/MS analysis. AMG-458 was more effective in cells that
expressed higher levels of c-Met/p-Met, suggesting that higher levels of c-
Met and p-Met in non-small cell lung cancer (NSCLC) tissue may classify
a subset of tumors that are more sensitive to molecular therapies against
this receptor. | [in vivo]
AMG-458 (orally, 30, 100 mg/kg) significantly inhibits tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight[1]. | Animal Model: | NIH-3T3/TPR-Met model and U-87 MG human glioblastoma xenograft model[1]. | | Dosage: | 10, 30, 100 mg/kg. | | Administration: | Orally q.d. or b.i.d. | | Result: | With an ED50 of ～12 mg/kg and an ED90 of ～ 34 mg/kg in NIH-3T3/TPR-Met model.
With an ED50 of ～16 mg/kg and an ED90 of ～ 59 mg/kg in U-87 MG human glioblastoma xenograft model.
Significantly inhibited tumor growth at 30 and 100 mg/kg q.d. and 30 mg/kg b.i.d. without adverse effect on body weight.
|
| Animal Model: | Balb/c mouse and SD rat[1]. | | Dosage: | 1 mg/kg (Pharmacokinetic Analysis). | | Administration: | IV dose: 1 mg/kg (20% Captisol with pH adjusted to 3.5 using methanesulfonic acid). | | Result: | Exhibited CL ((L/h)/kg) values of 0.16 and 0.73, Vss (L/kg) values of 0.31 and 0.62, t1/2 (h) values of 1.3 and 1.0 in mouse and rat, respectively. |
| [target]
c-Met (H1094R) | [IC 50]
VEGDR2: 4100 nM (Ki) | [References]
1. li b, torossian a, sun y, du r, dicker ap, lu b. higher levels of c-met expression and phosphorylation identify cell lines with increased sensitivity to amg-458, a novel selective c-met inhibitor with radiosensitizing effects. int j radiat oncol biol phys 2012,84:e525-531.2. liu l, siegmund a, xi n, kaplan-lefko p, rex k, chen a, et al. discovery of a potent, selective, and orally bioavailable c-met inhibitor: 1-(2-hydroxy-2-methylpropyl)-n-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-meth yl-3-oxo-2-phenyl-2,3-dihydro-1h-pyrazole-4-carboxamide (amg 458). j med chem 2008,51:3688-3691. |
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