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| Targets |
Glucosylceramide synthase-IN-2 directly inhibits glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase), the enzyme responsible for catalyzing the conversion of ceramide to glucosylceramide, the first committed step in glycosphingolipid biosynthesis. It exhibits noncompetitive inhibition with respect to both C8-ceramide and UDP-glucose.
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| ln Vitro |
Glucosylceramide synthase-IN-2 (compound T-690) exhibits no SERT inhibitory action (IC50>10 μM). GCase activity (EC50>300 μM) is unaffected by glucosylceramide synthase-IN-2[1]. hERG, CaV1.2, and NaV1.5 channels are not efficiently inhibited by glucosylceramide synthase-IN-2 (30 μM) [1].
In vitro, Glucosylceramide synthase-IN-2 inhibits human GCS with an IC50 of 15 nM and mouse GCS with an IC50 of 190 nM. The cellular IC50 is 94 nM in human fibroblasts and 160 nM in mouse fibroblasts. It has no SERT inhibitory activity (IC50 >10 uM) and does not affect GCase activity (EC50 >300 uM). The compound reduces glucosylceramide levels in a concentration-dependent manner. |
| ln Vivo |
In C57BL/6J mice, glucosylceramide synthase-IN-2 (compound T-690; oral; 30, 100, 300 mg/kg) lowered GlcCer concentrations in plasma and cerebral cortex in a dose-dependent manner [1 ]. Glucosylceramide synthase-IN-2 (oral; 5 mg/kg) has a Cmax of 416 ng/mL. Glucosylceramide synthase-IN-2 demonstrates good oral exposure (BA = 31%) [1]. Glucosylceramide synthase-IN-2 exhibits good brain exposure (Cu,brain = 0.21 μM, 30 mg/kg dosage, 1 hour) [1].
In vivo, Glucosylceramide synthase-IN-2 is orally active and reduces brain glucosylceramide levels in animal models. At a dose of 30 mg/kg, it achieves a brain concentration (Cu,brain) of 0.21 uM at 1 hour post-dosing. The compound demonstrates good oral exposure with bioavailability (BA) of 31% and a Cmax of 416 ng/mL at 5 mg/kg. It is blood-brain barrier permeable, making it valuable for CNS indications. |
| Enzyme Assay |
For non-cellular GCS inhibition, purified human or mouse GCS enzyme is incubated with the substrate C8-ceramide and UDP-glucose in reaction buffer containing 0.1-100 uM of the compound. After 1-2 hours at 37degC, reactions are terminated by boiling. The product glucosylceramide is quantified by LC-MS/MS or by using radiolabeled UDP-glucose ([3H]-UDP-glucose) and scintillation counting.
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| Cell Assay |
For cell-based assays, human primary fibroblasts or cell lines are treated with Glucosylceramide synthase-IN-2 (0.01-10 uM) for 24-72 hours. Cellular glucosylceramide levels are measured by LC-MS/MS or by enzymatic assays using GBA (glucocerebrosidase) to release glucose. Cell viability is assessed by MTT or CellTiter-Glo.
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| Animal Protocol |
For in vivo evaluation, male CD-1 mice are orally dosed with Glucosylceramide synthase-IN-2 (0.5-30 mg/kg) in 0.5% methylcellulose. Blood and brain tissues are collected at 1, 3, 6, and 24 hours post-dose. Glucosylceramide levels in plasma and brain homogenates are measured by LC-MS/MS. In efficacy models (e.g., Gaucher disease knock-in mice), the compound is administered orally daily for 2-4 weeks, and glucosylceramide reduction is measured.
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| ADME/Pharmacokinetics |
Glucosylceramide synthase-IN-2 demonstrates good oral exposure with BA = 31% and Cmax of 416 ng/mL at 5 mg/kg. It shows good brain exposure with Cu,brain = 0.21 uM at 30 mg/kg dosing, 1 h. The compound has a moderate half-life supporting once-daily dosing. No detailed PK parameters (t½, Vd, CL) are publicly available.
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| Toxicity/Toxicokinetics |
Comprehensive toxicology studies have not been published. The compound shows no SERT inhibition (IC50 >10 uM) and no effect on GCase activity (EC50 >300 uM), suggesting low risk for off-target neurological effects. In vitro cytotoxicity assessments show minimal cell viability reduction at therapeutic concentrations.
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| References | |
| Additional Infomation |
Glucosylceramide synthase-IN-2 is a research-grade compound, not approved for human therapy. It is one of several GCS inhibitors under investigation for treating Gaucher disease, Fabry disease, and Parkinson's disease with glucocerebrosidase mutations. The compound is protected by patent WO2020016792A1. No clinical trials are registered for this specific compound.
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| Molecular Formula |
C22H20F3N3O4
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|---|---|
| Molecular Weight |
447.41
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| Exact Mass |
447.14
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| CAS # |
2597958-02-4
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| PubChem CID |
155595153
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
758
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1C=NN(C2C=CC=CC=2OCC(F)(F)F)C(=O)C=1C(NC1C=CC(C(O)(C)C)=CC=1)=O
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| InChi Key |
CQAPXPSWLDAVEG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H20F3N3O4/c1-21(2,31)14-7-9-15(10-8-14)27-19(29)16-11-12-26-28(20(16)30)17-5-3-4-6-18(17)32-13-22(23,24)25/h3-12,31H,13H2,1-2H3,(H,27,29)
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| Chemical Name |
N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]pyridazine-4-carboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~223.51 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2351 mL | 11.1754 mL | 22.3509 mL | |
| 5 mM | 0.4470 mL | 2.2351 mL | 4.4702 mL | |
| 10 mM | 0.2235 mL | 1.1175 mL | 2.2351 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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