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检测方案
≥98% (HPLC)
质量水平
形式
powder
制造商/商品名称
Calbiochem®
储存条件
OK to freeze
protect from light
颜色
light orange
溶解性
DMSO: 2.5 mg/mL
储存温度
2-8°C
一般描述
A cell-permeable pyrazolopyrimidine-carboxamide compound that directly binds to glucocerebrosidase (GCase; Kd ~ 9 µM for NT-467 fluorescent labeled GCase) and enhances its activity and serves as a chaperone for its translocation to the lysosomal compartment in fibroblasts of patients with Gaucher disease (AC50 = 5.2 and 6.5 µM for wild type and mutant N370S, respectively). Also shown to be effective in increasing GCase activity in macrophages from Gaucher′s disease patients as well as in iPSC-derived macrophages (10.7 and 3.2 fold, respectively). Normalizes reactive oxygen species production and improves chemotaxis in Gaucher disease macrophages. Shown to permeate the blood-brain barrier. Exhibits desirable pharmacokinetic properties with plasma t1/2 = 19.3 h and Cmax of 1.03 µM (following a single injection of 50 mg/kg in mice).
A cell-permeable pyrazolopyrimidine-carboxamide that is shown to enhance cellular glucocerebrosidase (GCase) activity in monocyte- & iPSC-derived human macrophage cultures (hMAC & iMAC, respectively) from healthy donors as well as patients with Type I (GCase genotype N370S/N370S or N370S/c.84dupG) or Type II (GCase genotype IVS2+1G>A/L444P) Gaucher disease (GD) due to allosteric modulation of enzyme activity as well as restoration of mutant enzyme lysosomal localization, resulting in greatly enhanced lysosomal GCase substrates processing in GD cultures (%glucosylceremide reduction = 95% in IVS2+1G>A/L444P iMAC, 46.7% in N370S/c.84dupG iMAC, ≥50% in N370S/N370S hMAC & iMAC; %glucosylsphingosine reduction = 80% in IVS2+1G>A/L444P iMAC, ≥33% in N370S/N370S hMAC & iMAC; 8 µM for 6 d). NCGC00188758 treatment is also shown to reactivate ROS production upon phagocytosis of IgG-opsonized erythrocytes in both GD hMAC & iMAC cultures as well as iMAC chemotaxis toward SDF-1. Pharmacokinetic studies reveal good liver and brain exposure following single 50 mg/kg intraperitoneal injection in mice in vivo (Tmax/Cmax/T1/2 = 0.25 h/1.03 µM/19.3 h/plasma, 0.25 h/2.76 µM/18.2 h/brain, 0.25 h/17.29 µM/28.9 h) as well as mouse liver microsome stability (55% degradation in 60 min with NADPH) & Caco-2 permeability (6.0 x 10-6 cm s-1/A to B; 6.0 x 10-6 cm s-1/B to A) in vitro. Unlike the iminosugar-based chemical chaperone Isofagomine, NCGC00188758 does not inhibit GCase activity.
生化/生理作用
Cell permeable: yes
Primary Target
Glucocerebrosidase (Gcase)
Glucocerebrosidase (Gcase)
Reversible: yes
包装
Packaged under inert gas
警告
Toxicity: Standard Handling (A)
其他说明
Please note that the molecular weight for this compound is batch-specific due to variable water content.
法律信息
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
储存分类代码
11 - Combustible Solids
WGK
WGK 3
闪点(°F)
Not applicable
闪点(°C)
Not applicable
法规信息
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