N-{4-[(2-amino-3-chloropyridin-4-yl)oxy]-3-fluorophenyl}-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

• ChemBase编号: 72746
• 分子式: C25H19ClF2N4O4
• 平均质量: 512.8925664
• 单一同位素质量: 512.10628923
• SMILES: c1(c(nccc1Oc1ccc(cc1F)NC(=O)c1c(=O)n(ccc1OCC)c1ccc(cc1)F)N)Cl
• Canonical SMILES: CCOc1ccn(c(=O)c1C(=O)Nc1ccc(c(c1)F)Oc1ccnc(c1Cl)N)c1ccc(cc1)F
• InChI: InChI=1S/C25H19ClF2N4O4/c1-2-35-19-10-12-32(16-6-3-14(27)4-7-16)25(34)21(19)24(33)31-15-5-8-18(17(28)13-15)36-20-9-11-30-23(29)22(20)26/h3-13H,2H2,1H3,(H2,29,30)(H,31,33)
• InChIKey: VNBRGSXVFBYQNN-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: N-{4-[(2-amino-3-chloropyridin-4-yl)oxy]-3-fluorophenyl}-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
• IUPAC传统名: N-{4-[(2-amino-3-chloropyridin-4-yl)oxy]-3-fluorophenyl}-4-ethoxy-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide
• 别名: BMS777607; BMS-777607; BMS 777607

登记号

• CAS号: 1196681-44-3
• PubChem SID: 162037667
• PubChem CID: 24794418

理论计算性质

• Acid pKa: 12.823653
• 质子受体: 5
• 质子供体: 2
• LogD (pH = 5.5): 3.373697
• LogD (pH = 7.4): 3.9130704
• Log P: 3.928258
• 摩尔折射率: 132.7987 cm^3
• 极化性: 48.475723 Å^3
• 极化表面积: 106.78 Å^2
• 可自由旋转的化学键: 7
• 里宾斯基五规则: false

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: MEK

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S1561

Research Area

• Description: Cancer

Biological Activity

• Description: BMS-777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, respectively.
• Targets: c-Met; Axl; Ron; Tyro3
• IC50: 3.9 nM; 1.1 nM; 1.8 nM; 4.3 nM ^[1]
• In Vitro: BMS-777607 is a selective ATP-competitive Met kinase inhibitor which potently blocks the autophosphorylation of c-Met with IC50 of 20 nM in GTL-16 cell lysates, and demonstrates selective inhibition of proliferation in Met-driven tumor cell lines, such as GTL-16 cell line, H1993 and U87. ^[1] BMS-777607 inhibits hepatocyte growth factor (HGF)-triggered c-Met autophosphorylation with IC50 of <1 nm="" in="" pc-3="" and="" du145="" prostate="" cancer="" cells.="" bms="" 777607="" has="" little="" effect="" on="" tumor="" cell="" growth,="" but="" exhibits="" inhibitory="" effect="" on="" hgf-induced="" cell="" scattering="" in="" pc-3="" and="" du145="" cells,="" with="" almost="" complete="" inhibition="" at="" 0.5="" μm.="" bms="" 777607="" also="" suppresses="" stimulated="" cell="" migration="" and="" invasion="" in="" a="" dose-dependent="" fashion="" (ic50="">< 0.1="" μm)="" in="" both="" cell="" lines.="">^[2] Application of BMS 777607 (~10 μM) to the highly metastatic murine KHT cells for 2 hours potently eliminates basal levels of autophosphorylated c-Met with IC50 of 10 nM without affecting the total c-Met, leading to dose-dependent inhibition of phosphorylation of downstream signaling molecules including ERK, Akt, p70S6K and S6. Treatment with BMS-777607 (~1 μM) for 24 hours potently inhibits the KHT cell scatter, motility and invasion at doses in the nanomolar range which consists with MET gene knockdown, and modestly affects cell proliferation and colony formation. ^[3]
• In Vivo: Oral administration of BMS 777607 (6.25-50 mg/kg) significantly reduces tumor volumes of the GTL-16 human tumor xenografts in athymic mice with no observed toxicity. ^[1] Administration of BMS 777607 (25 mg/kg/day) decreases the number of KHT lung tumor nodules (28.3 ± 14.9 %, P<0.001), improves="" the="" morphological="" hemorrhage,="" and="" significantly="" impairs="" the="" metastatic="" phenotype="" in="" the="" 6–8="" week-old="" female="" c3h/hej="" mice="" injected="" with="" rodent="" fibrosarcoma="" kht="" cells="" without="" apparent="" systemic="" toxicity="" compared="" to="" the="" control="" treatment.="" a="" low="" dose="" of="" bms="" 777607="" (10="" mg/kg)="" also="" offers="" a="" mild="" but="" not="" significant="" inhibition="" of="" lung="" nodule="" formation="" compared="" to="" the="" vehicle="" control.="">^[3]
• Clinical Trials: Phase I/II has been completed in the study to find the maximum tolerated dose and the preliminary activity of BMS-777607 in subjects with advanced or metastatic solid tumors, hormone refractory prostate cancer, head and neck squamous cell carcinoma, and type I papillary renal cell carcinoma.
• Features: BMS 777607 is a potent inhibitor of Met family member, which is more than 40-fold selective versus Lck, VEGFR2, and TrkA/B and more than 500-fold selective versus all other receptor and nonreceptor kinases.

Protocol

• Protocol: Kinase Assay ^[4]
• Met Kinase Assay: The kinase reaction consists of baculovirus expressed GST-Met, 3 μg of poly(Glu/Tyr), 0.12 μCi ^33P γ-ATP, 1 μM ATP in 30 μL of kinase buffer (20 mM Tris-Cl, 5 mM MnCl2, 0.1 mg/mL BSA, 0.5 mM DTT). Reactions are incubated for 1 hour at 30 °C and stopped by the addition of cold trichloroacetic acid (TCA) to a final concentration of 8%. TCA precipitates are collected onto GF/C unifilter plates using a Filtermate universal harvester, and the filters are quantitated using a TopCount 96-well liquid scintillation counter. Dose response curves are generated to determine the concentration required to inhibit 50% of substrate phosphorylation (IC50). BMS 777607 is dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at 10 concentrations, in duplicate.
• Protocol: Cell Assay ^[3]
• Cell Lines: Rodent fibrosarcoma KHT cells
• Concentrations: Dissolved in DMSO as a stock solution (10 mM), final concentration ~10 μM.
• Incubation Time: 2, 24 and 96 hours
• Methods: KHT cells are exposed to serial dilution of BMS 777607 for 96 hours, then the MTT assay and trypan blue exclusion are used for the determination of cell proliferation and cell death, respectively. KHT cell colonies are incubated with BMS 777607 for 24 hours and then stained with crystal violet (0.1%) and photographed for the assessment of cell scattering. 2 mm scratch on the confluent KHT cell monolayer is made using a sterilized 1 ml pipette tip followed by treated with BMS-777607 for 24 hours, then the number of cells that have migrated into the denuded area is counted on 4 random fields for the evaluation of cell migration. For the examination of cell invasion, the commercial transwell inserts (8 μm pore membrane) pre-loaded with Matrigel are incubated with serum-free medium in the presence or absence of BMS 777607 at 37 °C for 2 hours to allow rehydration of Matrigel. Then cells suspended in serum-free medium are loaded onto the top chamber (5 × 10^3/insert) and complete medium (containing 10% FBS) is used in the lower chamber as a chemoattractant. After incubation for 24 hours, the Matrigel is removed and the inserts are stained with crystal violet. Invaded cells on the underside of the filter are photographed and counted.
• Protocol: Animal Study ^[3]
• Animal Models: Rodent fibrosarcoma KHT cells are established in female C3H/HeJ mice.
• Formulation: Dissolved in DMSO as a stock solution (10 mM).
• Doses: 10-25 mg/kg.
• Administration: Oral gavage once daily.

References

• References: [1] Schroeder GM, et al. J Med Chem, 2009, 52(5), 1251-1254.
• References: [2] Dai Y, et al. Mol Cancer Ther, 2010, 9(6), 1554-1561.
• References: [3] Dai Y, et al. Clin Exp Metastasis, 2012, 29, 253-261.
• References: [4] Kim KS, et al. J Med Chem, 2008, 51(17), 5330-5341.

参考文献

• Schroeder GM, et al. J Med Chem, 2009, 52(5), 1251-1254.
• Dai Y, et al. Mol Cancer Ther, 2010, 9(6), 1554-1561.
• Dai Y, et al. Clin Exp Metastasis, 2012, 29, 253-261.
• Kim KS, et al. J Med Chem, 2008, 51(17), 5330-5341.