GSK583CAS号: 1346547-00-9分子式: C20H19FN4O2S分子量: 398.45描述纯度储存/保存方法别名可溶性/溶解性靶点In vitro(体外研究)In vivo(体内研究)参考文献
产品描述 | |
描述 |
GSK583是一个高的强的,有选择性的RIP2激酶的抑制剂。 |
纯度 |
98% min
|
储存/保存方法 |
Store at -20℃ for one year(Powder);Store at 2-4℃ for two weeks;Store at -20℃ for six months after dissolution.
|
基本信息 | |
别名 |
GSK-583; GSK 583
|
可溶性/溶解性 |
DMSO 79 mg/mL (198.26 mM)
Ethanol 28 mg/mL (70.27 mM) Water slightly soluble or insoluble |
生物活性 | |
靶点 |
RIP2 ,RIP3
|
In vitro(体外研究) |
GSK583 possesses comparable binding affinity for RIP3 kinase as demonstrated by an in-house FP binding assay configured similarly to the RIP2 FP assay (RIP2 FP IC50 = 5 nM; RIP3 FP IC50 = 16 nM). Despite this potent biochemical activity against RIP3 kinase, GSK583 shows little or no inhibition of RIP3-dependent necroptotic cell death in a cellular assay up to 10 μM concentration. GSK583 potently and dose dependently inhibits MDP-stimulated tumor necrosis factor-alpha (TNFα) production with an IC50 = 8 nM in primary human monocytes. Following treatment with GSK583 at 1 μM, little inhibition of pro-inflammatory signaling is observed upon activation of Toll-like receptors (TLR2, TLR4, TLR7) or cytokine receptors (IL-1R, TNFR) but complete inhibition is observed upon activation of both NOD1 and NOD2 receptors, which signal in a RIP2-dependent manner. Although GSK583 has excellent kinase selectivity, it does inhibit both the hERG channel and Cyp3A4, which precludes it from further progression as a drug candidate.
|
In vivo(体内研究) |
GSK583 has low clearance, moderate volumes of distribution, and moderate oral bioavailability in both rat and mouse. Eventhough GSK583 would not produce a human phamacodynamic response within an acceptable dose range which precludes this molecule from further development as a drug candidate, the oral PK in rat and mouse provides sufficient systemic exposure for use as a preclinical in vivo tool molecule in an acute inflammation challenge model.
|
参考文献 | |
参考文献 |
[1]. Haile PA et al. The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase. J Med Chem, 2016 May 26, 59(10):4867-80
|
分子结构图