Brivanib (alaninate)
作者：齊岳
發布時間：2023-08-28
09:00:55
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產品名稱：Brivanib (alaninate)
產品描述：
| 產品描述 | Brivanib Alaninate is the alaninate salt of a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with potential antineoplastic activity. Brivanib strongly binds to and inhibits VEGFR2, a tyrosine kinase receptor expressed almost exclusively on vascular endothelial cells; inhibition of VEGFR2 may result in inhibition of tumor angiogenesis, inhibition of tumor cell growth, and tumor regression. |
| 靶點活性 | Flk1:89 nM, FGFR1:148 nM, VEGFR1:380 nM, VEGFR2:25 nM |
| 體外活性 | 25 mg/kg BMS-582664在大鼠中AUC為13.4 μM×hr,Cmax為6.4 μM.50 mg/kg BMS-582664在小鼠中AUC為136 μM×hr,Cmax為41 μM.50 mg/kg和100 mg/kg BMS-582664作用于攜帶病患衍生的移植瘤06-0606 的小鼠,抑制生長速度分別為55% 和13%.口服60 mg/kg BMS-582664顯著降低攜帶病患衍生的移植瘤06-0606 的小鼠中重量,促進細胞凋亡,降低微血管密度,抑制細胞增殖,并下調細胞周期調控.小鼠口服60 mg/kg BMS-582664,迅速吸收,Tmax為1小時,半衰期 (t1/2)為2.7小時,平均滯留時間為3.6小時.60 mg/kg和90 mg/kg BMS-582664劑量依賴性抑制攜帶H3396移植瘤的無胸腺小鼠中生長,生長抑制率分別為85%和97%.80 mg/kg和107 mg/kg.BMS-582664 處理攜帶L2987非小細胞肺*移植瘤的無胸腺小鼠,劑量依賴性抑制生長,生長抑制率分別為85% 和 97%.100 mg/kg BMS-582664抑制兩種攜帶移植瘤的小鼠模型（L2987和HCT116）中血管內皮細胞的增長. |
| 體內活性 | BMS-582664固態穩定性較高,在50°C下放置干燥劑的12周期間僅有0.3％降解,在pH為6.5時也具有較好的液態穩定性。2 μM BMS-582664明顯抑制VEGF和 bFGF刺激的SK-HEP1細胞和HepG-2細胞中VEGFR-2,FGFR-1,ERK1/2和Akt的磷酸化,而BMS-582664單獨作用于未經刺激的細胞,則不影響ERK1/2,Akt,VEGFR-2和FGFR-1的磷酸化水平。BMS-582664抑制VEGF和FGF刺激的HUVECs 增殖,IC50分別為40 nM和276 nM。BMS-582664抑制CYP2C19,CYP3A4(BFC)和CYP3A4 (BzRes)細胞,IC50分別為2.4 μM,0.51 μM和1.6 μM。 |
| 激酶實驗 | Kinase inhibition assays: For the VEGFR2, Flk1 and FGFR1 kinase assays, BMS-582664 is dissolved in DMSO and diluted with water/10% DMSO to a final DMSO concentration of 2%. The kinase reactions consists of 8 ng of enzymes with GST tag, 75 μg/mL substrate, 1 μM ATP, and 0.04 μCi [γ-33P]ATP in 50 μL total reaction volume (kinase buffer:? 20 mM Tris, pH 7.0, 25 μg/mL BSA, 1.5 mM MnCl2, 0.5 mM dithiothreitol). In all cases, the reactions are incubated for 60 min at 27℃ and terminated with the addition of cold trichloroacetic acid (TCA) to a final concentration of 15%. The percent inhibition from the kinase assays is determined by nonlinear regression analyses, and data are reported as the inhibitory concentration required to achieve 50% inhibition relative to control reactions (IC50). |
| 細胞實驗 | Cells are grown in 100 μL of minimal growth medium and 1.0% heat-inactivated fetal bovine serum in 96-well collagen IV coated plates at a density of 2 × 103 per well in a 37 ℃/5% CO2 environment. Twenty-four hours later, serum is adjusted to 10%, and BMS-582664 at various dilutions are added to each well in a final volume of minimal growth media that contains 10% serum. Forty-eight hours later, 0.5 μCi of [3H]thymidine is added in a volume of 20 μL of minimal media for 24 hours. Plates are washed once in PBS. Upon removal of PBS, Trypsin is added to cells which are subsequently harvested onto glass-fiber filters using an automated harvestor. Incorporated tritium is quantified using a β-counter. Dose?response curves are generated to determine the IC50 value, which is defined as the concentration of drug required to inhibit 50% of tritium incorporation when compared to untreated serum-stimulated cells.(Only for Reference) |
| 別名 | 丙氨酸布立尼布, BMS-582664, Brivanib Alaninate |
| 分子量 | 441.46 |
| 分子式 | C22H24FN5O4 |
| CAS No. | 649735-63-7 |
存儲
Powder: -20°C for 3 years | In solvent: -80°C for 2 years
溶解度
Ethanol: 82 mg/mL (185.7 mM)
DMSO: 82 mg/mL (185.7 mM)
( < 1 mg/mL refers to the product slightly soluble or insoluble )
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