GCase Activator, NCGC00188758

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.

Cell permeable: yes

Primary Target
Glucocerebrosidase (Gcase)

Reversible: yes

Packaged under inert gas

Please note that the molecular weight for this compound is batch-specific due to variable water content.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)