5.31660
GCase Activator, NCGC00188758
Synonym(s):
GCase Activator, NCGC00188758, N-(4-Ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide, Glucocerebrosidase Activator, Glucocerebrosidase Chemical Chaperone, NCGC758
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| Size/SKU | Availability | Price |
|---|---|---|
10 mg | Check Cart for Availability | $238.00 |
About This Item
Empirical Formula (Hill Notation):
C17H14N4O
Molecular Weight:
290.32
NACRES:
NA.77
UNSPSC Code:
12352200
Form:
powder
Assay:
≥98% (HPLC)
Solubility:
DMSO: 2.5 mg/mL
Color:
light orange
assay
≥98% (HPLC)
Quality Segment
form
powder
manufacturer/tradename
Calbiochem®
storage condition
OK to freeze, protect from light
color
light orange
solubility
DMSO: 2.5 mg/mL
storage temp.
2-8°C
General description
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.
Biochem/physiol Actions
Cell permeable: yes
Primary Target
Glucocerebrosidase (Gcase)
Glucocerebrosidase (Gcase)
Reversible: yes
Packaging
Packaged under inert gas
Other Notes
Please note that the molecular weight for this compound is batch-specific due to variable water content.
Legal Information
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
Disclaimer
Toxicity: Standard Handling (A)
Storage Class
11 - Combustible Solids
wgk
WGK 3
flash_point_f
Not applicable
flash_point_c
Not applicable
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