BR103354
BR103354 is an orally active, selective fibroblast activation protein (FAP) inhibitor with an IC50 value of 14 nM against hFAP. BR103354 restores the levels of phosphorylated ERK and Glut1 that are reduced by co-treatment with hFGF21 and FAP, decreases non-fasting blood glucose concentrations, improves glucose tolerance, and reduces hepatic triglyceride content. BR103354 ameliorates hepatic steatosis and hepatic fibrosis. BR103354 can be used in the research of type 2 diabetes and non-alcoholic steatohepatitis.
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- No. CAS: 2505339-87-5
- Fòrmula: C19H15F2N5O2S
- Peso molecular:415.42
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Descripciòn
IC50 & Target
[1]|
GLUT1 |
In Vitro
BR103354 (0.03 nM-100 μM; 60 min at 37°C) potently and selectively inhibits purified human FAP with an IC50 of 14 nM[1].
BR103354 inhibits serum FAP activity across mouse, cynomolgus monkey, and human samples with similar potency, with IC50 values ranging from 27 to 31 nM[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Differentiated 3T3/L1 adipocytes
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Concentration:5 μM
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Incubation Time:2 h (pre-incubation of hFGF21 with FAP; then added to cells)
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Result:Restored phosphorylated ERK and Glut1 levels that had been reduced by co-treatment of hFGF21 with FAP, matching levels observed with hFGF21 treatment alone.
Parmacokinetics
| Species | Dose | Route | Tmax | Cmax | T1/2 | Bioavailability |
|---|---|---|---|---|---|---|
| Mice[1] | 1 mg/kg | p.o. | 0.5 h | 2.3 μg/mL | 1.2 h | 48.4 % |
| Mice[1] | 5 mg/kg | p.o. | 0.5 h | 7.2 μg/mL | 1.1 h | 48.4 % |
| Mice[1] | 10 mg/kg | p.o. | 0.5 h | 19.2 μg/mL | 1.2 h | 48.4 % |
| Mice[1] | 100 mg/kg | p.o. | 1 h | 66.0 μg/mL | 4.0 h | 48.4 % |
| Mice[1] | 200 mg/kg | p.o. | 1 h | 122.5 μg/mL | 3.8 h | 48.4 % |
| Rat[1] | 10 mg/kg | p.o. | 1.1 h | 4.4 μg/mL | 3.5 h | / |
| Monkey[1] | 10 mg/kg | i.n. | 2.3 h | 0.42 μg/mL | 1.3 h | / |
| Monkey[1] | 30 mg/kg | i.n. | 2.3 h | 2.0 μg/mL | 2.8 h | / |
In Vivo
BR103354 (20-50 mg/kg; p.o.; once daily; for 4 consecutive weeks) reduces non-fasting blood glucose levels in ob/ob mice, inhibits FAP activity by ≥80%, increases serum FGF21 levels by approximately 1.4-fold, and simultaneously improves their insulin resistance, glucose tolerance, and hepatic steatosis[1].
BR103354 (50 mg/kg; intranasal administration) inhibits FAP activity by 65%-83% and increases the level of intact FGF21 in normal cynomolgus monkeys by 1.5-3.5 folds[1].
BR103354 (10-30 mg/kg; p.o.; once daily; for 10 consecutive weeks) inhibits FAP activity, increases serum FGF21 levels by 1.5-1.9 folds, reduces levels of hepatic enzymes and metabolic biomarkers, and ameliorates hepatic steatosis and fibrosis in CDAHFD-induced NASH mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:ob/ob (8-week-old male; spontaneous obese, diabetic model)[1]
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Dosage:20 mg/kg; 50 mg/kg
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Administration:p.o.; single dose
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Result:Reduced average nonfasting blood glucose to 178 mg/dL (20 mg/kg group) and 154 mg/dL (50 mg/kg group) at 3 hours post-administration.
Decreased blood glucose AUC by 40-45% relative to control.
Inhibited FAP activity by more than 70% at 1 hour post-administration, with inhibition maintained up to 9 hours.
Elevated plasma intact hFGF21 levels until 3 hours post-administration, then dropped below 10 ng/mL by 6 hours.
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Animal Model:ob/ob (8-week-old male; spontaneous obese, diabetic model)[1]
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Dosage:20 mg/kg; 50 mg/kg
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Administration:p.o.; once daily; 4 weeks
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Result:Significantly reduced nonfasting blood glucose levels starting at week 2 (P<0.01) and further reduced at week 3 (P<0.001) relative to vehicle.
Inhibited FAP activity by at least 80% at week 4 relative to vehicle.
Increased serum total FGF21 levels by approximately 1.4-fold at week 4.
Showed significantly improved glucose tolerance (reduced OGTT AUC) in the 50 mg/kg group.
Significantly reduced fasting body weight, liver weight, fasting blood glucose, insulin levels, and HOMA-IR relative to vehicle.
Significantly reduced serum ALT, AST, and total cholesterol levels; serum TG and NEFA levels were unaltered.
Decreased liver TG content, with reduced Oil Red O stained area relative to vehicle.
Reduced mRNA expression of lipogenesis/steatosis-related genes, and increased fatty acid oxidation-related genes (MCAD, PPARα) in liver.
Elevated white adipose tissue adiponectin mRNA expression.
Increased ERK phosphorylation in white adipose tissue relative to vehicle.
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Animal Model:C57BL/6J (5-week-old male; NASH induced by CDAHFD feeding for 4 weeks prior to treatment)[1]
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Dosage:10 mg/kg; 30 mg/kg
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Administration:p.o.; once daily; 10 weeks
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Result:Inhibited FAP activity in a dose-dependent manner relative to vehicle.
Increased serum FGF21 levels by 1.5-1.9-fold in treatment groups.
Reduced plasma ALT, AST, total cholesterol, TG, and glucose levels relative to vehicle.
Significantly reduced steatosis scores and Picrosirius red staining (fibrosis) relative to vehicle.
Chemical Information
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No. CAS 2505339-87-5
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Peso molecular 415.42
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Fòrmula C19H15F2N5O2S
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SMILES
O=C(C1=CSC(CC2=CC=C(C=C2)C#N)=N1)NCC(N3[C@@H](CC(F)(C3)F)C#N)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
BR103354 Related Classifications
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