AMG-458
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MedKoo CAT#: 205898

CAS#: 913376-83-7

Description: 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.

Chemical Structure

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AMG-458
CAS# 913376-83-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 205898
Name: AMG-458
CAS#: 913376-83-7
Chemical Formula: C30H29N5O5
Exact Mass: 539.22
Molecular Weight: 539.582
Elemental Analysis: C, 66.78; H, 5.42; N, 12.98; O, 14.83

Price and Availability

Size Price Availability Quantity
5mg USD 415 2 Weeks
10mg USD 750 2 Weeks
25mg USD 1250
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Synonym: AMG458; AMG-458; AMG 458

IUPAC/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

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:
Product Data
Instruction:
View handling instruction
Biological target: AMG 458 is a potent c-Met inhibitor with Ki of 1.2 nM, ~350-fold selectivity for c-Met than VEGFR2 in cells.
In vitro activity: When incubated with rat or human liver microsomes, AMG 458 exhibited covalent binding to proteins (Figure 2). The binding was NADPH-independent, indicating that metabolic activation was not taking place. The addition of GSH to the incubation medium did not cause a significant reduction in bound radioactivity. The binding was not reduced significantly when the enzyme was inactivated by heating, suggesting that the mechanism was not enzyme-dependent. To understand the nature of this covalent binding, we set out to determine the structure of the thioether adduct(s) formed. Reference: Chem Res Toxicol. 2008 Nov;21(11):2216-22. https://pubmed.ncbi.nlm.nih.gov/18837519/
In vivo activity: As a potent inhibitor of mouse c-Met (Ki = 2.0, IC50(CT26) = 120 nM; Table 2), 17 (AMG-458) was evaluated in the mouse liver pharmacodynamic assay. Oral dosing of 17 inhibited HGF-mediated c-Met phosphorylation in a dose-dependent manner with an approximate ED90 of 30 mg/kg and an associated plasma exposure of approximately 15 μM at 6 h (Figure 2A). There was a clear correlation between the inhibition of liver c-Met phosphorylation and the plasma concentration of 17. Reference: J Med Chem. 2008 Jul 10;51(13):3688-91. https://pubmed.ncbi.nlm.nih.gov/18553959/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 26.0 48.19

Preparing Stock Solutions

The following data is based on the product molecular weight 539.581760000000000000000000000000 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Teffera Y, Colletti AE, Harmange JC, Hollis LS, Albrecht BK, Boezio AA, Liu J, Zhao Z. Chemical reactivity of methoxy 4-o-aryl quinolines: identification of glutathione displacement products in vitro and in vivo. Chem Res Toxicol. 2008 Nov;21(11):2216-22. doi: 10.1021/tx800307n. PMID: 18837519. 2. Liu L, Siegmund A, Xi N, Kaplan-Lefko P, Rex K, Chen A, Lin J, Moriguchi J, Berry L, Huang L, Teffera Y, Yang Y, Zhang Y, Bellon SF, Lee M, Shimanovich R, Bak A, Dominguez C, Norman MH, Harmange JC, Dussault I, Kim TS. 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-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458). J Med Chem. 2008 Jul 10;51(13):3688-91. doi: 10.1021/jm800401t. Epub 2008 Jun 14. PMID: 18553959.
In vitro protocol: 1. Teffera Y, Colletti AE, Harmange JC, Hollis LS, Albrecht BK, Boezio AA, Liu J, Zhao Z. Chemical reactivity of methoxy 4-o-aryl quinolines: identification of glutathione displacement products in vitro and in vivo. Chem Res Toxicol. 2008 Nov;21(11):2216-22. doi: 10.1021/tx800307n. PMID: 18837519.
In vivo protocol: 1. Teffera Y, Colletti AE, Harmange JC, Hollis LS, Albrecht BK, Boezio AA, Liu J, Zhao Z. Chemical reactivity of methoxy 4-o-aryl quinolines: identification of glutathione displacement products in vitro and in vivo. Chem Res Toxicol. 2008 Nov;21(11):2216-22. doi: 10.1021/tx800307n. PMID: 18837519. 2. Liu L, Siegmund A, Xi N, Kaplan-Lefko P, Rex K, Chen A, Lin J, Moriguchi J, Berry L, Huang L, Teffera Y, Yang Y, Zhang Y, Bellon SF, Lee M, Shimanovich R, Bak A, Dominguez C, Norman MH, Harmange JC, Dussault I, Kim TS. 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-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458). J Med Chem. 2008 Jul 10;51(13):3688-91. doi: 10.1021/jm800401t. Epub 2008 Jun 14. PMID: 18553959.

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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 Nov 15;84(4):e525-31. doi: 10.1016/j.ijrobp.2012.06.025. Epub 2012 Jul 24. PubMed PMID: 22836051. 2: Liu L, Norman MH, Lee M, Xi N, Siegmund A, Boezio AA, Booker S, Choquette D, D'Angelo ND, Germain J, Yang K, Yang Y, Zhang Y, Bellon SF, Whittington DA, Harmange JC, Dominguez C, Kim TS, Dussault I. Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series. J Med Chem. 2012 Mar 8;55(5):1868-97. Epub 2012 Feb 24. PubMed PMID: 22320327. 3: Tiedt R, Degenkolbe E, Furet P, Appleton BA, Wagner S, Schoepfer J, Buck E, Ruddy DA, Monahan JE, Jones MD, Blank J, Haasen D, Drueckes P, Wartmann M, McCarthy C, Sellers WR, Hofmann F. A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. Cancer Res. 2011 Aug 1;71(15):5255-64. Epub 2011 Jun 22. PubMed PMID: 21697284. 4: Foti RS, Rock DA, Wienkers LC, Wahlstrom JL. Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos. 2010 Jun;38(6):981-7. Epub 2010 Mar 4. PubMed PMID: 20203109. 5: Teffera Y, Colletti AE, Harmange JC, Hollis LS, Albrecht BK, Boezio AA, Liu J, Zhao Z. Chemical reactivity of methoxy 4-o-aryl quinolines: identification of glutathione displacement products in vitro and in vivo. Chem Res Toxicol. 2008 Nov;21(11):2216-22. PubMed PMID: 18837519. 6: Liu L, Siegmund A, Xi N, Kaplan-Lefko P, Rex K, Chen A, Lin J, Moriguchi J, Berry L, Huang L, Teffera Y, Yang Y, Zhang Y, Bellon SF, Lee M, Shimanovich R, Bak A, Dominguez C, Norman MH, Harmange JC, Dussault I, Kim TS. 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 Jul 10;51(13):3688-91. Epub 2008 Jun 14. PubMed PMID: 18553959.