7-methoxy-4-({6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl}methoxy)quinoline

• ChemBase编号: 5707
• 分子式: C22H17N5O2
• 平均质量: 383.40268
• 单一同位素质量: 383.13822481
• SMILES: n1c(c2ccccc2)ccc2nnc(COc3c4c(cc(cc4)OC)ncc3)n12
• Canonical SMILES: COc1ccc2c(c1)nccc2OCc1nnc2n1nc(cc2)c1ccccc1
• InChI: InChI=1S/C22H17N5O2/c1-28-16-7-8-17-19(13-16)23-12-11-20(17)29-14-22-25-24-21-10-9-18(26-27(21)22)15-5-3-2-4-6-15/h2-13H,14H2,1H3
• InChIKey: HEAIZQNMNCHNFD-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 7-methoxy-4-({6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl}methoxy)quinoline
• IUPAC传统名: 7-methoxy-4-({6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl}methoxy)quinoline
• 别名: 7-methoxy-4-[(6-phenyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy]quinoline; AMG-208

登记号

• CAS号: 1002304-34-8
• PubChem SID: 160969134; 99444550
• PubChem CID: 24864821

理论计算性质

JChem

• 质子受体: 6
• 质子供体: 0
• LogD (pH = 5.5): 2.6945014
• LogD (pH = 7.4): 3.3418026
• Log P: 3.3655484
• 摩尔折射率: 119.5413 cm^3
• 极化性: 43.732964 Å^3
• 极化表面积: 74.43 Å^2
• 可自由旋转的化学键: 5
• 里宾斯基五规则: true

ALOGPS 2.1

• Log P: 3.66
• LOG S: -4.52
• 溶解度: 1.15e-02 g/l

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: c-Met

产品相关信息

• 成盐信息: Free Base

详细说明

DrugBank - DB08079

Drug information: experimental

Selleck Chemicals - S1316

Research Area

• Description: Solid tumours

Biological Activity

• Description: AMG-208 is a highly selective c-Met inhibitor with IC50 of 9.3 nM.
• Targets: c-Met
• IC50: 9.3 nM ^[1]
• In Vitro: AMG-208 shows the potent inhibition of kinase c-Met activity with IC50 of 9 nM in a cell-free assay. Besides, AMG-208 treatment also leads to the inhibition of HGF-mediated c-Met phosphorylation in PC3 cells with IC50 of 46 nM. ^[1]Incubation of AMG-208 with rat and human liver microsomes in the presence of NADPH qualitatively yields C6-phenylarene oxidation products as the major metabolites. ^[1] Pre-incubation of AMG-208 with human liver microsomes for 30 minutes shows a potent time-dependent inhibition for CYP3A4 metabolic activity with IC50 of 4.1 μM, which is an eightfold decrease relative to the IC50 (32 μM) without preincubation. ^[2] AMG-208 is identified to be a c-MET and RON dual selective inhibitor. ^[3]
• In Vivo: In male Sprague?Dawley rats, AMG-208 (0.5 mg/kg i.v.) shows a high bioavailability with Cl of 0.37 L/h/kg, V_ss of 0.38 L/kg and T_1/2 of 1 hour, while AMG-208 (2 mg/kg i.v.) shows a bioavailability with AUC_0→∞ of 2517 ng·h/mL and F of 43%, respectively. ^[1]
• Clinical Trials: AMG-208 is currently in Phase I clinical trials in patients with Advanced Solid Tumors.

Protocol

• Protocol: Kinase Assay ^[1]
• In Vitro Kinase Assay: IC50 measurements versus c-Met kinase and its mutants are determined using homogenous time-resolved fluorescence (HTRF) assays. AMG-208 is tested in a 10-point dose-response curve for each enzyme using an ATP concentration of two-thirds K_m for each. Most assays consists of enzyme mixed with kinase reaction buffer [20 mM Tris-HCl (pH 7.5), 10 mM MgCl₂, 5 mM MnCl₂, 100 mM NaCl, 1.5 mM EGTA]. A final concentration of 1 mM DTT, 0.2 mM NaVO₄, and 20 μg/mL BSA is added before each assay. For all assays, 5.75 mg/mL streptavidin-allophycocyanin and 0.1125 nM Eu-PT66 are added immediately before the HTRF reaction. Plates are incubated for 30 minutes at room temperature and read on a Discovery instrument Molecules are tested in a 10-point serial dilution for each c-Met construct using an ATP concentration of two thirds Km value that is determined for each enzyme preparation and calculated using the Eadie-Hofstee and Lineweaver-Burke methods.
• Protocol: Animal Study ^[1]
• Animal Models: Male Sprague-Dawley rats
• Formulation: AMG-208 is dissolved in DMSO.
• Doses: ≤2 mg/kg
• Administration: Administered via i.v. and p.o.

References

• References: [1] Albrecht BK, et al. J Med Chem. 2008, 51(10), 2879-2882.
• References: [2] Boezio AA, et al. Bioorg Med Chem Lett. 2009, 19(22), 6307-6312.
• References: [3] Liu X, et al. Trends Mol Med. 2010,16(1), 37-45.

参考文献

• Albrecht BK, et al. J Med Chem. 2008, 51(10), 2879-2882.
• Boezio AA, et al. Bioorg Med Chem Lett. 2009, 19(22), 6307-6312.
• Liu X, et al. Trends Mol Med. 2010,16(1), 37-45.