531660 GCase Activator, NCGC00188758 - Calbiochem

531660
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      Overview

      Replacement Information

      Key Specifications Table

      Empirical Formula
      C₁₇H₁₄N₄O

      Pricing & Availability

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      5.31660.0001
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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
          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.

          Brochure

          Title
          NPI Flyer- Epigenetics and Nuclear Function Feature (EMD)
          New Products - Antibodies, Small Molecule, Inhibitors

          Technical Info

          Title
          White Paper: Further considerations of antibody validation and usage. (EMD)
          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.