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| Targets |
EMD638683 R-Form selectively targets serum- and glucocorticoid-regulated kinase 1 (SGK1). SGK1 is a member of the AGC kinase family (PKA/PKG/PKC) and is regulated by phosphorylation via the PI3K/PDK1/mTORC2 pathway. SGK1 plays crucial roles in regulating epithelial sodium channel (ENaC) activity, cellular ion homeostasis, cell cycle progression, apoptosis, and fibrotic responses. Overexpression and hyperactivation of SGK1 have been implicated in hypertension, cardiac hypertrophy, renal fibrosis, diabetic nephropathy, and cancer. EMD638683 is highly selective for SGK1 with an IC₅0 of 3 microM, showing minimal activity against other AGC kinases including PKB/Akt, PKA, and PKC.
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| ln Vitro |
In vitro, EMD638683 (the racemic or enantiomeric forms) inhibits SGK1 activity with an IC₅0 of 3 microM. The compound has been tested in human cervical carcinoma HeLa cells by determining SGK1-dependent phosphorylation of downstream targets such as NDRG1 (N-myc downstream-regulated gene 1). EMD638683 concentration-dependently reduces NDRG1 phosphorylation, confirming target engagement in cellular systems. The compound shows selectivity for SGK1 over other kinases, including PKB/Akt, with minimal off-target effects. The R-form likely exhibits similar or slightly different potency compared to the racemic mixture or S-form, depending on the stereospecificity of binding to the SGK1 ATP-binding pocket.
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| ln Vivo |
In vivo, EMD638683 has been studied in animal models to evaluate its effects on fluid balance, electrolyte excretion, and body weight. In rodent studies, EMD638683 administration tended to increase fluid intake and urinary excretion of sodium (Na+), significantly increased urinary flow rate, and significantly decreased body weight. These effects are consistent with SGK1 inhibition-mediated modulation of ENaC activity in the kidney, leading to natriuresis and diuresis. The compound has been proposed as a potential template for drugs counteracting hypertension in individuals with type 2 diabetes or metabolic syndrome, where SGK1 is upregulated. Further in vivo studies are needed to fully characterize the pharmacokinetics and tissue distribution of the R-form.
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| Enzyme Assay |
In vitro enzyme assays for EMD638683 R-Form involve measuring SGK1 kinase activity using recombinant human SGK1 enzyme and a peptide substrate (e.g., a peptide derived from NDRG1 or a generic kinase substrate) in the presence of ATP. The assay is performed in kinase buffer containing Mg2+ or Mn2+. Varying concentrations of EMD638683 (0.001-100 microM) are incubated with the enzyme and substrate at 30degC for 30-60 minutes. Kinase activity is quantified by measuring phosphorylated substrate using a fluorescence-based or luminescence-based detection system (e.g., ADP-Glo or HTRF). IC₅0 values are determined from dose-response curves. Selectivity profiling is performed against a panel of kinases to confirm specificity.
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| Cell Assay |
Cellular assays for EMD638683 R-Form are performed using cell lines that express SGK1, such as HeLa, HEK293, or MCF-7 cells. Cells are cultured in appropriate medium and seeded in 6- or 96-well plates. Following serum starvation to reduce basal SGK1 activity, cells are treated with serial dilutions of EMD638683 (0.1-100 microM) for 2-24 hours. SGK1 activity is assessed by Western blotting for phosphorylation of its downstream substrate NDRG1 at Ser328/Thr346. Alternatively, a luciferase reporter assay driven by the SGK1-responsive promoter can be used. Cell viability and proliferation are measured using MTT or CellTiter-Glo assays. Apoptosis is evaluated by caspase-3/7 activity or Annexin V staining.
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| Animal Protocol |
In vivo animal studies for EMD638683 have been conducted in rodent models to assess effects on renal function and blood pressure. In typical protocols, male Sprague-Dawley rats or C57BL/6 mice are administered EMD638683 orally or intraperitoneally at doses of 10-50 mg/kg. Animals are placed in metabolic cages for urine collection over 24-hour periods. Urine volume, sodium excretion, potassium excretion, and creatinine clearance are measured. Blood pressure is monitored using tail-cuff plethysmography or telemetry. Body weight, food intake, and water intake are recorded daily. At study termination, blood and tissue samples (kidney, heart, liver) are collected for pharmacokinetic and biomarker analysis.
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| ADME/Pharmacokinetics |
EMD638683 R-Form (CAS#: 1184940-47-3) has molecular formula C1₈H1₈F2N2O4 and molecular weight 364.34. The compound is soluble in DMSO at 100 mg/mL. Storage recommendations: powder form at -20degC for up to 3 years, 4degC for 2 years; in solution at -80degC for 6 months or -20degC for 1 month. The compound is a research chemical intended for laboratory use only. The R-form and S-form of EMD638683 may exhibit different pharmacokinetic properties including absorption, distribution, metabolism, and elimination due to stereospecific interactions with metabolic enzymes and transporters. Further characterization of the individual enantiomers is ongoing.
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| Toxicity/Toxicokinetics |
Toxicological information for EMD638683 R-Form is limited as the compound is a research chemical. Based on its mechanism of SGK1 inhibition, potential toxicities may include electrolyte disturbances (hyponatremia, hyperkalemia), hypotension, and effects on renal function. The compound should be handled with standard laboratory precautions including the use of personal protective equipment (gloves, lab coat, safety goggles) and working in a well-ventilated fume hood. Avoid inhalation, ingestion, and skin contact. The compound should be stored as recommended and disposed of according to institutional waste management guidelines. No specific toxicity data (LD₅0, mutagenicity, carcinogenicity) are available in the public literature.
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| References | |
| Additional Infomation |
EMD638683 R-Form (CAS#: 1184940-47-3) is a highly selective SGK1 inhibitor with an IC₅0 of 3 microM, representing the (R)-enantiomer of the compound. SGK1 is a key regulator of epithelial sodium channels and has emerged as a therapeutic target for hypertension, fibrosis, and metabolic disorders. EMD638683 has been investigated as a potential template for drugs counteracting hypertension in individuals with type 2 diabetes. The compound is supplied as a research chemical for laboratory use only. The two enantiomers (R-form and S-form) are available for stereospecific studies of SGK1 inhibition. As of the current date, EMD638683 and its enantiomers remain preclinical research compounds and have not been approved for clinical use.
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| Molecular Formula |
C₁₈H₁₈F₂N₂O₄
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| Molecular Weight |
364.34
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| Exact Mass |
364.123
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| CAS # |
1184940-47-3
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| Related CAS # |
EMD638683;1181770-72-8;EMD638683 S-Form;1184940-46-2
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| PubChem CID |
66577016
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| Appearance |
Off-white to pink solid powder
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| LogP |
3.267
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
498
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CCC1=C(C=CC(=C1C)O)C(=O)NNC(=O)[C@@H](C2=CC(=CC(=C2)F)F)O
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| InChi Key |
SSNAPUUWBPZGOY-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C18H18F2N2O4/c1-3-13-9(2)15(23)5-4-14(13)17(25)21-22-18(26)16(24)10-6-11(19)8-12(20)7-10/h4-8,16,23-24H,3H2,1-2H3,(H,21,25)(H,22,26)/t16-/m1/s1
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| Chemical Name |
N'-[(2R)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]-2-ethyl-4-hydroxy-3-methylbenzohydrazide
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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 : ~66.67 mg/mL (~182.99 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 3.33 mg/mL (9.14 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 33.3 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: 3.33 mg/mL (9.14 mM) 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; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 33.3 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: 3.33 mg/mL (9.14 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7447 mL | 13.7234 mL | 27.4469 mL | |
| 5 mM | 0.5489 mL | 2.7447 mL | 5.4894 mL | |
| 10 mM | 0.2745 mL | 1.3723 mL | 2.7447 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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