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BMS-626529

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Catalog No.
A3253
HIV-1吸附的抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 1,500.00
现货
10mg
¥ 2,500.00
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50mg
¥ 7,500.00
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200mg
¥ 15,000.00
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Background

EC50

HIV-1 attachment inhibitors represent a new class of entry inhibitors that prevent the initial interaction between virus and host cell by binding to the viral envelope protein gp120 and blocking attachment of the virus to the CD4 receptor on CD4+ T-cells. BMS-626529 is a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4+ T-cells.

In vitro: The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. BMS-626529 had half-maximal effective concentration values of6 log10, with half-maximal effective concentration values in the low pM range against the most susceptible viruses. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life [1].

In vivo: No animal in-vivo data available currently

Clinical trial: BMS-663068 is a prodrug of the small-molecule inhibitor BMS-626529. The maximum median decreased in plasma HIV-1 RNA load from baseline ranged from 1.21 to 1.73 log10 copies/mL. Plasma concentrations of BMS-626529 were not associated with an antiviral response, while low baseline inhibitory concentrations and the minimum and average steady-state BMS-626529 plasma concentrations, when adjusted by the baseline protein binding–adjusted 90% inhibitory concentration, were linked with antiviral response. BMS-663068 was generally well tolerated [2].

References:
[1] Nowicka-Sans B, Gong YF, McAuliffe B, Dicker I, Ho HT, Zhou N, Eggers B, Lin PF, Ray N, Wind-Rotolo M, Zhu L, Majumdar A, Stock D, Lataillade M, Hanna GJ, Matiskella JD, Ueda Y, Wang T, Kadow JF, Meanwell NA, Krystal M.  In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068. Antimicrob Agents Chemother. 2012;56(7):3498-507.
[2] Nettles RE, Schürmann D, Zhu L, Stonier M, Huang SP, Chang I, Chien C, Krystal M, Wind-Rotolo M, Ray N, Hanna GJ, Bertz R, Grasela D.  Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J Infect Dis. 2012;206(7):1002-11.

文献引用

1. Stadtmueller BM, Bridges MD, et al. "DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions."Immunity. 2018 Aug 21;49(2):235-246.e4. PMID:30076100
2. Pancera M, Lai YT, et al. "Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529." Nat Chem Biol. 2017 Oct;13(10):1115-1122. PMID:28825711

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt473.48
Cas No.701213-36-7
FormulaC24H23N7O4
SynonymsBMS 626529;BMS626529
Solubility≥1.48 mg/mL in DMSO, <2.42 mg/mL in EtOH, <2.39 mg/mL in H2O
Chemical Name1-(4-benzoylpiperazin-1-yl)-2-[4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]ethane-1,2-dione
SDFDownload SDF
Canonical SMILESCC1=NN(C=N1)C2=NC=C(C3=C2NC=C3C(=O)C(=O)N4CCN(CC4)C(=O)C5=CC=CC=C5)OC
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验[1]:

结合实验

使用MicroBioSpin 6 columns测量[3H]BMS-626529与gp120的结合。平衡含有25 mM Tris-HCl(pH 7.5)、125 mM NaCl、50nM gp120JRFL和[3H]BMS-626529的系列稀释液的结合溶液(30 μl),然后吸附到MicroBioSpin 6 column上。将柱子离心(14,000 rpm)5分钟,收集洗脱液,用闪烁计数器测定放射性。为了测量解离动力学,将150nM [3H] BMS-626529与60nM gp120在环境温度下温育1小时以实现结合平衡,然后加入摩尔过量14倍的可溶性CD4蛋白以驱动解离。在指定的时间间隔取等分试样,吸附到离心柱上,离心,定量洗脱液中的放射性。将来自含有和不含可溶性CD4攻击的平行样品的氚信号进行比较,测定化合物结合的百分比。

细胞实验 [1]:

细胞系

感染HIV-1临床分离株的PBMC;MT-2和PM1细胞

溶解方法

可溶于DMSO。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月

反应条件

6天;溶于100%二甲基亚砜(DMSO)中,并序列稀释至所需浓度,使得细胞培养实验中的最终DMSO浓度为1%。

实验结果

在来自不同人类组织如MT-2型T淋巴细胞、HEK293(肾)、PM1和PBMC的几种细胞类型中,BMS-626529表现出低细胞毒性。BMS-626529对CXCR4-向性LAI病毒的EC50值为0.7 nM,具有广谱的活性。

临床实验 [2]:

疾病模型

感染乙型HIV-1的成人,年龄≥18岁。

剂量

600 mg或1200 mg,含或不含100mg利托那韦;8天;口服给药。

实验结果

BMS-663068是BMS-626529的前体药物,可以降低血浆HIV-1的RNA水平,并增加CD4+ T细胞的平均绝对值。此外,BMS-663068具有良好的耐受性。给予前体药物BMS-663068后,BMS-626529具有良好的药代动力学特性。

注意事项

请测试室内所有化合物的溶解度,实际溶解度可能与理论值略有不同。这是由实验系统错误引起的,这是正常的。

References:

[1]. Nowicka-Sans B, Gong YF, McAuliffe B, et al. In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068. Antimicrob Agents Chemother, 2012, 56(7): 3498-3507.

[2]. Nettles RE, Schürmann D, Zhu L, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infe cted subjects. J Infect Dis, 2012, 206(7): 1002-1011.

生物活性

描述 BMS-626529是HIV-1 gp120的小分子吸附抑制剂,作用于HIV-1亚型A、B和C的外壳蛋白,IC50值分别为2.26 nM、0.34 nM和1.3 nM。
靶点 HIV-1 subtype A envelope HIV-1 subtype B envelope HIV-1 subtype C envelope      
IC50 2.26 nM 0.34 nM 1.3 nM      

质量控制

化学结构

BMS-626529

相关生物数据

BMS-626529

相关生物数据

BMS-626529