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SU5416

A tyrosine kinase inhibitor

原价
¥587-7550
价格
470-6040
SU5416的二维码

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  • 货号: ajci14856
  • CAS: 204005-46-9,194413-58-6
  • 别名: 司马沙尼; SU5416; Semaxanib
  • 分子式: C15H14N2O
  • 分子量: 238.28
  • 纯度: >98%
  • 溶解度: ≥ 11.9 mg/mL in DMSO
  • 储存: Desiccate at -20°C
  • 库存: 现货

Background

SU5416 is a potent small molecule vascular endothelial growth factor receptor (VEGFR) inhibitor. SU5416 is a 3-substituted indolin-2-one compound with relatively high specificity for VEGFR-2 and VEGFR-1, used extensively in animal models of PH, primarily due to effects on pulmonary vascular endothelial cell apoptosis and proliferation.[1] SU416 has been developed for the treatment of solid human tumors as well. [3]


In vitro study was performed to examine the inhibitory effect of SU5416 on KDR phosphorylation. Which indicated that pretreatment of BCECs with SU5416 resulted in a dose-dependent inhibition of KDR phosphorylation with an IC50 of 0.29 ± 0.071 μM (n=6) SU5416 almost completely inhibited KDR phosphorylation at the concentration of 3 μM. Few BCECs were stained with trypan blue after the treatment of SU5416, at least up to the concentration of 3 μM for 24 h. This suggested that the inhibitory effect of SU5416 on KDR phosphorylation was not due to the cell toxicity.[2]


In vivo study demonstrated that SU5416 could significantly reverse LPS-induced ALI in mice, and exert better protective effect in TLR4 knockout mice. SU5416 could also act as a protective agent against LPS-induced ALI in mice. Moreover, SU5416 dramatically restored the reduction of CD31 expression mediated by LPS, suggesting SU5416 could rescue LPS-induced dysfunction of pulmonary endothelial barrier. In addition, both p-VEGFR2 and VEGFR2 expressions were inhibited by SU5416 in WT and TLR4?/- mice. SU5416 could attenuate LPS-induced ALI through modulating the VEGF/VEGFR and NF-κB pathways, which suggested SU5416 might be used for the treatment of patients with inflammation-mediated ALI.[3]

参考文献:
[1]. Peloquin GL, et al. SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model. Respir Res. 2019 Jun 17;20(1):123.
[2] Takeda A, et al. Suppression of experimental choroidal neovascularization utilizing KDR selective receptor tyrosine kinase inhibitor. Graefes Arch Clin Exp Ophthalmol. 2003 Sep;241(9):765-72.
[3]. Huang X, et al. SU5416 attenuated lipopolysaccharide-induced acute lung injury in mice by modulating properties of vascular endothelial cells. Drug Des Devel Ther. 2019 May 23;13:1763-1772.


SU5416 是一种有效的小分子血管内皮生长因子受体 (VEGFR) 抑制剂。 SU5416 是一种 3-取代的二氢吲哚-2-酮化合物,对 VEGFR-2 和 VEGFR-1 具有相对较高的特异性,广泛用于 PH 动物模型,主要是由于对肺血管内皮细胞凋亡和增殖的影响。 [1] SU416 也已开发用于治疗实体人类肿瘤。 [3]


进行了体外研究以检查 SU5416 对 KDR 磷酸化的抑制作用。这表明用 SU5416 预处理 BCECs 导致 KDR 磷酸化的剂量依赖性抑制,IC50 为 0.29 ± 0.071 μM (n=6) SU5416 在 3 μM 的浓度下几乎完全抑制 KDR 磷酸化。在 SU5416 处理后,很少有 BCEC 被台盼蓝染色,至少达到 3 μM 的浓度 24 小时。这表明SU5416对KDR磷酸化的抑制作用不是由于细胞毒性。[2]


体内研究表明,SU5416 可显着逆转 LPS 诱导的小鼠 ALI,并对 TLR4 基因敲除小鼠发挥更好的保护作用。 SU5416 还可以作为 LPS 诱导的小鼠 ALI 的保护剂。此外,SU5416 显着恢复了 LPS 介导的 CD31 表达降低,表明 SU5416 可以挽救 LPS 诱导的肺内皮屏障功能障碍。此外,在 WT 和 TLR4-/- 小鼠中,p-VEGFR2 和 VEGFR2 表达均被 SU5416 抑制。 SU5416可通过调节VEGF/VEGFR和NF-κB通路减轻LPS诱导的ALI,提示SU5416可用于治疗炎症介导的ALI。[3]

Protocol

Cell experiment [1]:

Cell lines

Human microvascular endothelial cells of the lung-blood (HMVEC-LBl)

Preparation Method

Cells were plated into 24-well plates and grown to confluence in EGM-2MV medium containing 2.5% FBS plus supplements. Only cells in passage 5 were used, with n = 12 wells per experimental condition.

Reaction Conditions

HMVEC-LBl was exposed to human VEGF-121 (40 ng/mL) in-vitro in serum-free medium for 7 h, in the absence or presence of the VEGF receptor antagonist, SU5416 (3 and 10 μM).

Applications

SU5416 can block the effects of VEGF and completely prevent VEGFR2 phosphorylation as well. There was no evidence of background VEGFR2 phosphorylation in the HMVEC-LBl and in serum-free medium. Adding SU5416 did not affect the background phosphorylation. In the absence of VEGF, SU5416 increased ET-1 production, by 16% at 10 μM, and SU5416 can completely abolish the VEGF effect on ET-1 production.

Animal experiment [2]:

Animal models

Wild-type C57BL/6 mice (male, 8–10 weeks, 20–24 g) and genetically engineered TLR4-de?cient mice (male, 8–10 weeks, 20–22 g)

Preparation Method

Mice were stimulated by intratracheal administration of LPS after anesthetization with an intraperitoneal (i.p.) injection of tribromoethanol. Isopyknic saline-treated mice served as blank control group. After LPS stimulation, the experimental mice were treated with SU5416, DXM or DXM + SU5416 by oral administration for 12 hours. DXM-treated mice were served as positive control group.

Dosage form

20 mg/kg, BW solution in DMSO

Applications

SU5416 could be implemented to suppress immune response in mice with ALI. Normally, excessive activation and penetration of neutrophils is the common pathological process in LPS-induced ALI. Which subsequently enhanced the release of proinflammatory cytokines, which can further aggravate lung injury. SU5416 exhibited inhibitory effect on the population of neutrophil cell (P

参考文献:

[1]. Star GP, et al. Effects of vascular endothelial growth factor on endothelin-1 production by human lung microvascular endothelial cells in vitro. Life Sci. 2014 Nov 24;118(2):191-4.


[2]. Huang X, et al. SU5416 attenuated lipopolysaccharide-induced acute lung injury in mice by modulating properties of vascular endothelial cells. Drug Des Devel Ther. 2019 May 23;13:1763-1772.

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