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ln Vitro |
In THP-1 cells, GDC-2394 (20 μM; 30 min) prevents the production of apoptosis associated speck-like protein containing CARD (ASC) specks generated by NLRP3[1]. After the NLRP3 inflammasome is activated, GDC-2394 (1 nM-10 μM; 7 d) suppresses the generation of IL-1β and IL-18 by human macrophages[1]. In addition to inhibiting NLRP3-dependent IL-1β release (IC50=63 nM) and NLRC4-dependent IL-1β release (IC50>20 μM) in mouse bone marrow-derived macrophages (mBMDMs), GDC-2394 (0-20 μM; 30 min) also suppresses caspase-1 activation in THP-1 cells[1].
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ln Vivo |
In an acute mouse peritonitis model, GDC-2394 (compound 20) (1 mg/kg, 10 mg/kg; po; single dose) suppresses the production of IL-1β[1]. In a functional rat model of gouty arthritis, GDC-2394 (25 mg/kg; once daily for 7 days) is effective in reducing paw edema and pain[1]. GDC-2394's preclinical PK[1]. Mouse Rat Dog Cyno CLp (mL/min/kg) 10.1 1.3 11.7 4.1 Vss (L/kg) 0.72 0.29 0.67 0.18 T1/2 (h) 1.2 4.4 0.99 0.89 %F (1 mg/kg) 80 33 78 53 Instances
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Animal Protocol |
Animal/Disease Models: Acute mouse peritonitis model[1]
Doses: 1 mg/kg and 10 mg/kg Route of Administration: po (oral gavage); 2 h later treated with 1.25 μg LPS (ip) followed by 1 mg monosodium urate crystals (ip) a further 2 h later. Experimental Results: Resulted in a dose-dependent decrease in peritoneal IL-1β concentrations after MSU treatment, and diminished the level of IL-1β by 66.8 and 81.3% at 1 and 10 mg/kg compared with the control. Animal/Disease Models: Functional rat model of gouty arthritis[1] Doses: 25 mg/kg Route of Administration: Interventional injection; one time/day for 7 days Experimental Results: Dramatically inhibited knee swelling after 48 h. |
References |
[1]. McBride C, et al. Overcoming Preclinical Safety Obstacles to Discover (S)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor. J Med Chem. 2022 Oct 24.
[2]. Stafford, et al. Preparation of hexahydroindacenylcarbamoyldihydropyrazolooxazinesulfonamide derivatives and analogs for use as interleukin-1 activity inhibitors: World Intellectual Property Organization, WO2018136890[P]. 2018-07-26. |
Molecular Formula |
C20H25N5O4S
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Molecular Weight |
431.51
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CAS # |
2238822-07-4
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Related CAS # |
2238822-11-0 (R-isomer);2238822-07-4 (S-isomer);
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Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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SMILES |
O1C[C@@H](NC)CN2N=CC(S(NC(NC3=C4C(=CC5CCCC3=5)CCC4)=O)(=O)=O)=C12
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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 |
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 : 50 mg/mL (115.87 mM)
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.82 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 20.8 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: ≥ 2.08 mg/mL (4.82 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.3174 mL | 11.5872 mL | 23.1744 mL | |
5 mM | 0.4635 mL | 2.3174 mL | 4.6349 mL | |
10 mM | 0.2317 mL | 1.1587 mL | 2.3174 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.