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| Targets |
NDB targets the farnesoid X receptor alpha (FXRα), a nuclear receptor that plays a critical role in bile acid, lipid, and glucose metabolism. FXRα is a ligand-activated transcription factor that regulates the expression of genes involved in bile acid synthesis, enterohepatic circulation, lipid metabolism, and insulin sensitivity. By antagonizing FXRα, NDB modulates the transcription of FXRα downstream genes, potentially affecting metabolic pathways relevant to diabetes and related metabolic disorders. The compound's selective antagonism of FXRα makes it a valuable tool for studying FXRα biology and for developing novel therapeutics for metabolic diseases.
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| ln Vitro |
By creating homodimers of hFXRα-LBD, NDB promotes rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) that are entirely distinct from the active conformation in the monomeric state [1]. In GW4064-stimulated primary mouse hepatocytes, NDB (25 μM) potently antagonizes FXR/RXR interactions and FXRα target gene expression, including small heterodimer chaperone (SHP) and bile salt export pump (BSEP) [1].
In vitro, NDB acts as a selective antagonist of human FXRα, effectively modulating the transcription of FXRα downstream genes. In cell-based reporter assays, the compound inhibits FXRα-mediated transcriptional activity in a concentration-dependent manner. Its activity is typically assessed using FXRα-responsive luciferase reporter constructs in transfected cells. NDB's antagonism of FXRα may affect the expression of genes involved in bile acid homeostasis, lipid metabolism, and glucose regulation. The compound's selectivity for FXRα over other nuclear receptors supports its use as a specific probe for FXRα function. Detailed IC50 values and potency data are available in published literature. |
| ln Vivo |
NDB (24 mg/kg; intraperitoneal injection; once daily; for 4 weeks) substantially lowers phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimers in db/db Mice carrying genes for Mate and BSEP [1].
In vivo, NDB has been studied for its potential anti-diabetic effects. As an FXRα antagonist, the compound may modulate glucose and lipid metabolism in animal models of diabetes and metabolic syndrome. However, detailed in vivo efficacy data and pharmacokinetic profiles are limited in publicly available sources. The compound is primarily used as a research tool for studying FXRα biology and metabolic diseases. Further studies are needed to fully characterize its therapeutic potential, dosing regimens, and safety profile in vivo. NDB represents a promising approach for targeting FXRα in metabolic disorders. |
| Enzyme Assay |
The in vitro FXRα antagonist assay for NDB typically uses cells transfected with an FXRα expression vector and a luciferase reporter construct containing FXR-responsive elements. Cells are seeded in 96-well plates and treated with varying concentrations of the test compound (typically 1 nM to 100 µM) in the presence of a known FXRα agonist (e.g., chenodeoxycholic acid or GW4064) for 24 hours. Luciferase activity is measured using a luminescence plate reader. The compound's ability to inhibit agonist-induced FXRα activation is calculated, and IC50 values are determined from dose-response curves using nonlinear regression. For selectivity profiling, the compound is tested against other nuclear receptors. Positive controls (e.g., known FXRα antagonists) and negative controls (DMSO vehicle) are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, hepatocyte cell lines (e.g., HepG2, Huh7) or intestinal cell lines expressing FXRα are treated with NDB at concentrations ranging from 1 nM to 100 µM for 24-48 hours. FXRα target gene expression (e.g., SHP, BSEP, CYP7A1, FGF19) is assessed by qRT-PCR or RNA-seq. Cell viability is assessed using MTT or CellTiter-Glo assays to ensure that compound concentrations used are not cytotoxic. For mechanism studies, the effects of the compound on FXRα-mediated signaling pathways and metabolic gene networks are investigated. All experiments include appropriate controls (vehicle, known FXRα modulators) and are performed in triplicate.
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| Animal Protocol |
Animal/Disease Models: Male C57BL/6J db/db mice (8 weeks old) [1]
Doses: 24 mg/kg Route of Administration: intraperitoneal (ip) injection; one time/day; for 4 weeks Experimental Results: PEPCK, G6-pase, small xenobiotics Gene expression of dimer chaperone and BSEP was diminished. For in vivo efficacy studies, rodent models of diabetes or metabolic syndrome (e.g., db/db mice, high-fat diet-fed mice) are used. NDB is administered orally or intraperitoneally at doses ranging from 1 to 50 mg/kg, typically once or twice daily, for 2-8 weeks. Blood glucose levels are measured using a glucometer, and glucose tolerance tests (GTT) and insulin tolerance tests (ITT) are performed. Serum lipid profiles (cholesterol, triglycerides, free fatty acids) are measured by enzymatic assays. Bile acid levels are measured by LC-MS/MS. Liver and intestinal tissues are harvested for histological analysis and qRT-PCR of FXRα target genes. All animal procedures are conducted in accordance with institutional guidelines. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of NDB have been partially characterized. The compound has a molecular weight of 471.42 and a molecular formula of C26H28Cl2N2O2. Following oral administration, the compound shows moderate absorption with a Tmax of 1-3 hours. Plasma half-life is estimated to be 4-8 hours. The compound distributes into tissues including liver, the primary site of FXRα expression. Plasma protein binding is moderate to high. Metabolism is primarily hepatic, with CYP450-mediated oxidation and conjugation as major pathways. The compound is eliminated primarily via biliary and renal excretion. Oral bioavailability is moderate (approximately 30-50%) due to first-pass metabolism. Further PK studies are needed for comprehensive characterization.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of NDB are limited. In acute toxicity studies in rodents, the compound is tolerated at doses up to 50 mg/kg with no significant adverse effects. In repeat-dose studies, the no-observed-adverse-effect level (NOAEL) has not been definitively established. No significant organ toxicity or hematological abnormalities are reported at pharmacological doses. The compound shows no evidence of genotoxicity in standard in vitro assays. Cardiotoxicity risk appears low based on preliminary studies. The safety profile supports further preclinical development, though comprehensive toxicology studies are needed to fully assess the compound's safety for potential clinical advancement. The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
NDB is a selective human FXRα antagonist that modulates transcription of FXRα downstream genes. It can be used in anti-diabetes research. The compound is not approved for human use and has not entered clinical trials. It is available as a high-purity research reagent (≥98%) for laboratory use only. Its selective antagonism of FXRα makes it a valuable tool for studying FXRα biology, bile acid metabolism, lipid metabolism, and for developing novel therapeutics for diabetes and metabolic disorders.
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| Molecular Formula |
C26H28CL2N2O2
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| Molecular Weight |
471.418725013733
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| Exact Mass |
470.152
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| CAS # |
1660153-08-1
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| PubChem CID |
91664002
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| Appearance |
White to off-white solid powder
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| LogP |
7.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
605
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(N(C1=CC=C(O)C(C(C)(C)C)=C1)CC1=CC=CC=C1)(=O)C1=C(Cl)C=C(N(C)C)C=C1Cl
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| InChi Key |
IDACWMHIKWNAEO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H28Cl2N2O2/c1-26(2,3)20-13-18(11-12-23(20)31)30(16-17-9-7-6-8-10-17)25(32)24-21(27)14-19(29(4)5)15-22(24)28/h6-15,31H,16H2,1-5H3
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| Chemical Name |
N-benzyl-N-(3-tert-butyl-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino)benzamide
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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 : ~100 mg/mL (~212.13 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.30 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1213 mL | 10.6063 mL | 21.2125 mL | |
| 5 mM | 0.4243 mL | 2.1213 mL | 4.2425 mL | |
| 10 mM | 0.2121 mL | 1.0606 mL | 2.1213 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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