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GSK2269557
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
GSK2269557图片
CAS NO:1254036-77-5
规格:98%
分子量:477
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议

产品介绍
inhibitor of PI3Kδ
CAS:1254036-77-5
分子式:C26H28N6O ? HCl
分子量:477
纯度:98%
存储:Store at -20°C

Background:

pKi : 9.9


GSK2269557 is an inhibitor of PI3Kδ.


Phosphoinositide 3-kinase delta (PI3Kδ), a lipid kinase belonging to the Class 1 PI3K family, catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate to produce the critical signalling molecule phosphatidylinositol-3,4,5-triphosphate and then triggers various downstream biological events that ultimately regulate cell proliferation, growth, differentiation, chemotaxis and survival.


In vitro: In the screening study, GSK2269557 met the original potency goal in the PBMC assay (pIC50 >9) and showed exquisite selectivity against the PI3K isoforms in a modified HTRF assay. Moreover, GSK2269557 could induce concentration-dependent increases in QT interval and Tpe at 0.3 and 1 μM and an increase in QRS at 1 μM, however, no treatment-related TdP arrhythmias were seen [1].


In vivo: In a disease relevant Brown Norway Rat acute OVA model of Th2 driven lung inflammation, GSK2269557 was found to be albe to protect against eosinophil recruitment with an ED50 of 67 μg/kg. The activity of GSK2269557 was also assessed using other endpoints, leukocyte recruitment to the lung (neutrophils, macrophages, CD4 and CD8 T-lymphocytes at 48 hours) and Th2 cytokines such as IL-13. It was found that GSK2269557 could reduce recruitment of all leukocyte subpopulations and IL-13 in the lungs in a dose-dependent manner [1].


Clinical trial: GSK2269557 was investigated in a double blind and placebo controlled trial in healthy males and smokers. It was found that GSK2269557 was well tolerated in healthy males. There was a low incidence of AE’s and the plasma PK was well defined confirming high levels of drug within the lung compared to plasma [2].


参考文献:
[1] Down, K. ,Amour, A.,Baldwin, I.R., et al. Optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase δ for the treatment of respiratory disease. J. Med. Chem. 58(18), 7381-7399 (2015).
[2] Robert Wilson, Anthony Cahn, Amanda Deans, Iain McSherry, Curtis Rambaran, Ana Sousa, Darren Wilbraham.  Safety, tolerability and pharmacokinetics (PK) of single and repeat nebulised doses of a novel phosphoinositide 3-kinase δ inhibitor (PI3Kδ), GSK2269557, administered to healthy male subjects in a phase I study. European Respiratory Journal 2013 42: P729.