531660 GCase Activator, NCGC00188758 - Calbiochem

531660
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Overview

Replacement Information

Key Specifications Table

Empirical Formula
C₁₇H₁₄N₄O

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      Glass bottle 10 mg
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      Description
      OverviewA 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).

      Please note that the molecular weight for this compound is batch-specific due to variable water content.
      Catalogue Number531660
      Brand Family Calbiochem®
      SynonymsN-(4-Ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide, Glucocerebrosidase Activator, Glucocerebrosidase Chemical Chaperone, NCGC758
      References
      ReferencesAflaki, E., et al. 2014. Sci. Transl. Med. 6, 240ra73.
      Patnaik, S., et al. 2012. J. Med. Chem. 55, 5734.
      Product Information
      FormLight orange powder
      Hill FormulaC₁₇H₁₄N₄O
      Chemical formulaC₁₇H₁₄N₄O
      ReversibleY
      Quality LevelMQ100
      Applications
      Biological Information
      Primary TargetGlucocerebrosidase (Gcase)
      Purity≥98% by HPLC
      Physicochemical Information
      Cell permeableY
      Dimensions
      Materials Information
      Toxicological Information
      Safety Information according to GHS
      Safety Information
      Product Usage Statements
      Storage and Shipping Information
      Ship Code Ambient Temperature Only
      Toxicity Standard Handling
      Storage +2°C to +8°C
      Protect from Light Protect from light
      Do not freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.
      Packaging Information
      Packaged under inert gas Packaged under inert gas
      Transport Information
      Supplemental Information
      Specifications

      Documentation

      GCase Activator, NCGC00188758 - Calbiochem SDS

      Title

      Safety Data Sheet (SDS) 

      References

      Reference overview
      Aflaki, E., et al. 2014. Sci. Transl. Med. 6, 240ra73.
      Patnaik, S., et al. 2012. J. Med. Chem. 55, 5734.
      Data Sheet

      Note that this data sheet is not lot-specific and is representative of the current specifications for this product. Please consult the vial label and the certificate of analysis for information on specific lots. Also note that shipping conditions may differ from storage conditions.

      Revision19-December-2014 JSW
      SynonymsN-(4-Ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide, Glucocerebrosidase Activator, Glucocerebrosidase Chemical Chaperone, NCGC758
      DescriptionA 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.
      FormLight orange powder
      Intert gas (Yes/No) Packaged under inert gas
      Chemical formulaC₁₇H₁₄N₄O
      Purity≥98% by HPLC
      SolubilityDMSO (2.5 mg/ml)
      Storage +2°C to +8°C
      Protect from light
      Do Not Freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.
      Toxicity Standard Handling
      ReferencesAflaki, E., et al. 2014. Sci. Transl. Med. 6, 240ra73.
      Patnaik, S., et al. 2012. J. Med. Chem. 55, 5734.