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
• Empirical Formula (Hill Notation): C₁₇H₁₄N₄O
• Molecular Weight: 290.32
• UNSPSC Code: 12352200
• NACRES: NA.77

Properties

• Assay: ≥98% (HPLC)
• Quality Level: 100
• 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

Description

General description

A cell-permeable pyrazolopyrimidine-carboxamide compound that directly binds to glucocerebrosidase (GCase; K_d ~ 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 t_1/2 = 19.3 h and C_max 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 (T_max/C_max/T_1/2 = 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)

Reversible: yes

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

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

Safety Information

• Storage Class Code: 11 - Combustible Solids
• WGK: WGK 3
• Flash Point(F): Not applicable
• Flash Point(C): Not applicable