Glucosylceramide synthase-IN-2 (compound T-690) is a potent, BBB (blood-brain barrier) permeable/penetrable and orally bioactive glucosylceramide synthase (GCS) inhibitor (antagonist) with IC50 of 15 for human GCS and 15 for mouse GCS respectively. nM and 190 nM. Glucosylceramide synthase-IN-2 noncompetitively inhibits C8 ceramide and UDP glucose. Glucosylceramide synthase-IN-2 may be used in Gaucher disease study.

Physicochemical Properties

Molecular Formula	C22H20F3N3O4
Molecular Weight	447.41
Exact Mass	447.14
CAS #	2597958-02-4
PubChem CID	155595153
Appearance	Light yellow to yellow solid powder
LogP	2.9
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	6
Heavy Atom Count	32
Complexity	758
Defined Atom Stereocenter Count	0
SMILES	C1C=NN(C2C=CC=CC=2OCC(F)(F)F)C(=O)C=1C(NC1C=CC(C(O)(C)C)=CC=1)=O
InChi Key	CQAPXPSWLDAVEG-UHFFFAOYSA-N
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)
Chemical Name	N-[4-(2-hydroxypropan-2-yl)phenyl]-3-oxo-2-[2-(2,2,2-trifluoroethoxy)phenyl]pyridazine-4-carboxamide
HS Tariff Code	2934.99.9001
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)

Biological Activity

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].
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].
References	[1]. Discovery of Brain-Penetrant Glucosylceramide Synthase Inhibitors with a Novel Pharmacophore. J Med Chem. 2022 Mar 10;65(5):4270-4290.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~223.51 mM)

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.