BIIB042
BIIB042 is a potent, orally active, brain-penetrant, and selective γ-secretase modulator (GSM). BIIB042 reduces Aβ42 and increases Aβ38 levels in cells. BIIB042 significantly reduces brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. BIIB042 reduces Aβ42 levels and Aβ plaque burden in Tg2576 mice. BIIB042 can be used for alzheimer's disease (AD) research.
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- No. CAS: 1257396-73-8
- Fòrmula: C29H29F4NO2
- Peso molecular:499.54
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
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Chemical Information
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Actividad biológica
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| CHO | EC50 |
0.15 μM
Compound: 10a
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Modulation of gamma-secretase in CHO cells overexpressing APP V717 mutant assessed as increase in amyloid beta38 level after 17 hrs by ELISA
Modulation of gamma-secretase in CHO cells overexpressing APP V717 mutant assessed as increase in amyloid beta38 level after 17 hrs by ELISA
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[PMID: 24900267] |
| CHO | EC50 |
0.17 μM
Compound: 10a
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Modulation of gamma-secretase in CHO cells overexpressing APP V717 mutant assessed as reduction in amyloid beta42 level after 17 hrs by ELISA
Modulation of gamma-secretase in CHO cells overexpressing APP V717 mutant assessed as reduction in amyloid beta42 level after 17 hrs by ELISA
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[PMID: 24900267] |
| H4 | EC50 |
70 nM
Compound: 10a
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Modulation of gamma-secretase in human H4 cells expressing wild type APP assessed as reduction in amyloid beta42 level
Modulation of gamma-secretase in human H4 cells expressing wild type APP assessed as reduction in amyloid beta42 level
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[PMID: 24900267] |
BIIB042 (compound 10a) inhibits COX1 and COX2 very weakly (IC50 = 35 and 27 μM, respectively) and exhibits weak inhibition of the hERG channel (IC50 = 15 μM)[1].
BIIB042 exhibits good cellular permeability and is not a substrate for efflux transporters[1].
BIIB042 demonstrates good metabolic stability in liver microsomes and does not inhibit major cytochrome P450 enzymes[1].
BIIB042 (3-30 μM, 20 h) has no effect on HES-1 protein levels in MC-IXC cells, indicating its selective action on amyloid precursor protein processing without impacting Notch signaling[2].
BIIB042 (20 h) reduces the levels of Aβ42 (IC50 = 64.3 nM), increased the levels of Aβ38 (EC50 = 146 nM) and has little effect on the levels of Aβ40 in H4-APP cells[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:MC-IXC cells
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Concentration:3, 10 and 30 μM
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Incubation Time:20 h
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Result:Did not alter HES1 protein levels.
| Species | Dose | Route | CLplasma | Vss | T1/2 | AUC0-24 | Cmax | Tmax | F |
|---|---|---|---|---|---|---|---|---|---|
| Cynomolgus Monkey[1] | 1 mg/kg | i.v. | 3.7 mL/min/kg | 1.7 L/kg | 11.2 h | 4.7 μg·h/mL | / | / | / |
| Cynomolgus Monkey[1] | 10 mg/kg | p.o. | / | / | 25 h | 48 μg·h/mL | 5.9 μg/mL | 2.0 h | 106 % |
| Dog[1] | 1 mg/kg | i.v. | 14 mL/min/kg | 0.9 L/kg | 1.3 h | 1.2 μg·h/mL | / | / | / |
| Dog[1] | 10 mg/kg | p.o. | / | / | 2.3 h | 5.2 μg·h/mL | 1.4 μg/mL | 1.3 h | 44 % |
| Rat[1] | 1 mg/kg | i.v. | 1.5 mL/min/kg | 0.8 L/kg | 7.2 h | 10.4 μg·h/mL | / | / | / |
| Rat[1] | 10 mg/kg | p.o. | / | / | 6.6 h | 49.7 μg·h/mL | 6.0 μg/mL | 1.7 h | 47 % |
BIIB042 (0.3-30 mg/kg, p.o. (in diet), daily for 6 months) significantly decreases Aβ42 levels in brain, and reduces parenchymal amyloid plaque burden of Tg2576 mice[2].
BIIB042 (0-100 mg/kg, i.g., single dose) dose-dependently lowers Aβ42 and elevates Aβ38 in the brain and plasma of CF-1 mice, demonstrating a potent and brain-penetrant GSM profile[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Tg2576 mice (5 months old)[2]
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Dosage:0, 3, 10, 30 and 60 mg/kg
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Administration:p.o. (in diet), daily for 65 days
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Result:Significantly increased Aβ38 levels in brain in a dose-dependent manner.
Significantly decreased Aβ42 levels in brain in a dose-dependent manner.
Showed no significant changes in levels of Aβ40.
Significantly reduced insoluble Aβ42 at 10, 30 and 60 mg/kg compared to vehicle.
Showed no significant changes in insoluble Aβ38.
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Animal Model:Tg2576 mice (10 months old)[2]
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Dosage:0.3,1,10 and 30 mg/kg
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Administration:p.o. (in diet), daily for 6 months
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Result:Significantly reduced soluble and insoluble Aβ42 levels in the brain and plasma at 30 mg/kg.
Significantly reduced parenchymal amyloid plaque burden in both the cortex and hippocampus at 30 mg/kg.
Showed a trend towards increased Aβ levels at 0.3 and 1 mg/kg.
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Animal Model:CF-1 mice[2]
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Dosage:0, 3, 10, 30 and 100 mg/kg
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Administration:i.g., single dose
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Result:Induced significant and dose-dependent decreases in Aβ42 at all tested doses.
Showed a dose-dependent increases in Aβ38 at 10, 30 and 100 mg/kg.
Induced Aβ pharmacodynamic responses in plasma, with similar effects as in brain with decreases in Aβ42, increases in Aβ38 and small changes in Aβ40 at higher doses.
Brain concentrations were approximately 80% of plasma concentrations at the 4 h time point across all doses.
Chemical Information
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No. CAS 1257396-73-8
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Peso molecular 499.54
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Fòrmula C29H29F4NO2
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SMILES
OC([C@H](C)C(C=C1)=CC(C2=CC=C(C(F)(F)F)C=C2)=C1[C@H](N3CCC(C)CC3)C4=CC=C(F)C=C4)=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
[1]. Peng H, et al. Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator. ACS Med Chem Lett. 2011 Aug 5;2(10):786-91. [Content Brief]
[2]. Scannevin RH, et al. BIIB042, a novel γ-secretase modulator, reduces amyloidogenic Aβ isoforms in primates and rodents and plaque pathology in a mouse model of Alzheimer's disease. Neuropharmacology. 2016 Apr;103:57-68. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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