FXR antagonist 5
FXR antagonist 5 is an orally active FXR antagonist with an IC50 of 11.79 μM. FXR antagonist 5 stimulates GLP-1 secretion in enteroendocrine cells and decreases NR0B2 mRNA expression. FXR antagonist 5 improves glycemic control in HFD/STZ-induced diabetic mice and shows a trend toward improved glucose tolerance, increases circulating GLP-1 and insulin levels, and ameliorates dyslipidemia as well as markers of hepatic and renal injury. FXR antagonist 5 can be used for research on type 2 diabetes.
Nur für Forschungszwecke. Wir verkaufen nicht an Patienten.
- Formel: C37H62N4O4
- Molecular Weight:626.91
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
Biologische Aktivität
Beschreibung
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| HEK293 | IC50 |
16.49 μM
|
Antagonism of FXR-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
Antagonism of FXR-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
|
acs.jmedchem.6c02247 |
| HEK293 | IC50 |
33.44 μM
|
Inhibition of PXR-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
Inhibition of PXR-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
|
acs.jmedchem.6c02247 |
| HEK293 | IC50 |
34.05 μM
|
Inhibition of LXRα-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
Inhibition of LXRα-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
|
acs.jmedchem.6c02247 |
| HEK293 | IC50 |
31.26 μM
|
Inhibition of RXRα-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
Inhibition of RXRα-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
|
acs.jmedchem.6c02247 |
| HEK293 | IC50 |
20.76 μM
|
Inhibition of PPARγ-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
Inhibition of PPARγ-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
|
acs.jmedchem.6c02247 |
| HEK293 | IC50 |
44.92 μM
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Inhibition of VDR-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
Inhibition of VDR-dependent transcriptional activity in transiently transfected HEK293 cells by dual-luciferase reporter assay after 2 hrs pretreatment and 24 hrs agonist incubation.
|
acs.jmedchem.6c02247 |
| NCI-H716 | IC50 |
44.50 μM
|
Cytotoxicity against human NCI-H716 enteroendocrine cells assessed as viability reduction by CCK-8 assay after 2 hrs incubation.
Cytotoxicity against human NCI-H716 enteroendocrine cells assessed as viability reduction by CCK-8 assay after 2 hrs incubation.
|
acs.jmedchem.6c02247 |
In Vitro
FXR antagonist 5 (0.195-100 μM; 2 h pre-incubation, 24 h after addition of agonist) antagonizes FXR in HEK293 reporter gene assays with an IC50 of 16.49 μM and shows moderate selectivity over other nuclear receptors[1].
FXR antagonist 5 (5-20 μM; 2 h) strongly stimulates GLP-1 secretion in NCI-H716 cells with low cytotoxicity (IC50 44.50 μM)[1].
FXR antagonist 5 (5-20 μM; 72 h) decreases NR0B2 mRNA expression in NCI-H716 cells at 20 μM without altering FGF19 expression[1].
FXR antagonist 5 shows good gastrointestinal and microsomal stability in vitro, but has a high plasma protein binding and CYP2D6/CYP3A4 inhibition risk; moreover, at 10 μM, it has minimal inhibitory effect on hERG current in CHO-hERG cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:NCI-H716 cells
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Concentration:5, 10, and 20 μM
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Incubation Time:72 h
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Result:An overall concentration-related reduction in NR0B2 mRNA expression occurred, with reduction observed at 20 μM.
FGF19 expression was not altered.
Parmacokinetics
| Species | Dose | Route | Cmax | AUC0-t | Tmax | T1/2 |
|---|---|---|---|---|---|---|
| Rat[1] | 50 mg/kg | p.o. | 93.50 μg/L | 660.55 h·μg/L | 0.80 h | 17.53 h |
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6J (initial body weight 18 g; 7‑week high‑fat/high‑carbohydrate diet priming; ~30 g body weight, 8‑h fasting, 3‑cycle 30 mg/kg i.p. STZ (HY-13753); blood‑glucose assessed 1‑week post‑STZ, maintained 2‑week re‑evaluation)
[1] -
Dosage:100 mg/kg
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Administration:p.o.; once daily; 35 days
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Result:Recorded lower daily food (10.92 g) and water intake (25.06 g/day) in week 5, compared with 14.50 g food and 37.21 g/day water for the model group.
Measured fasting blood glucose at 15.23 mmol/L on day 35.
Observed reduced two‑hour postprandial blood glucose on days 7, 21, and 35.
Calculated an OGTT AUC of 3248.82 mmol·min/L on day 27, versus 3442.31 mmol·min/L in the model group.
Detected terminal GSP at 6.14 mmol/L, compared with 7.71 mmol/L for the model group.
Found elevated plasma GLP‑1 (7.73 pM) and insulin (61.07 pg/mL), relative to model‑group values of 6.45 pM and 50.77 pg/mL.
Documented reduced plasma TC and TG levels versus the model group.
Noted a trending decrease in plasma total bile acids; the model group displayed a modest increase relative to normal animals.
Obtained ALT of 83.62 U/L (model: 127.83 U/L) and AST of 95.51 U/L (model: 139.81 U/L).
Measured decreased plasma creatinine compared with the model group.
Identified ameliorated hepatic cellular edema, fatty change and vacuolization via H&E staining, alongside diminished hepatic lipid‑droplet accumulation in Oil Red O staining.
Detected alleviated glomerular enlargement, tubular dilation and vacuolar degeneration in kidney histological sections.
Chemical Information
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Molecular Weight 626.91
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Formel C37H62N4O4
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SMILES
CC1(C)CC[C@]2(C(OCCCC(C)(C3=NN=NN3)C)=O)CC[C@@]4(C)[C@]5(C)CCC6C(C)(C)[C@@H](O)CC[C@]6(C)C5CC(O)C4C2C1
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)