BMS 433796
(Synonyms: (ALPHAS)-N-[(1S)-2-[[(5S)-4,5-二氢-3-甲基-4-氧代-3H-2,3-苯并二氮杂卓-5-基]氨基]-1-甲基-2-氧代乙基]-3,5-二氟-ALPHA-羟基苯乙酰胺) 目录号 : GC31012
BMS433796是一种γ-分泌酶抑制剂，用于阿尔茨海默氏病转基因小鼠模型，可降低Aβ活性。
Cas No.:935525-13-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | The binding assay is performed in duplicate in an assay volume of 250 μl consisting of 25 μL of buffer (50 mM HEPES and 0.1% CHAPSO, pH 7.0) or 10 μM BMS-433796 to define nonspecific binding, 25 μL of buffer containing [3H]IN973, and 200 μL of homogenate (200 μg of protein). Incubation is initiated by the addition of the membrane homogenates at 25°C for 1 h. Binding reactions are terminated by filtration through Whatman GF/B filters using a cell harvester. Unbound radioactivity is removed by rinsing the filters with ice-cold wash buffer (PBS; pH 7.0). Filters are counted using a 2500TR liquid scintillation counter. Saturation data are analyzed by the nonlinear regression analysis program LIGAND. Binding curves are best fit to a one-site model, yielding the equilibrium dissociation constant (Kd) and the maximal number of binding sites (Bmax)[2]. |
References: [1]. Prasad CV, et al. Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): a gamma-secretase inhibitor with Abeta lowering activity in a transgenic mouse model of Alzheimer's disease. Bioorg Med Chem Lett. 2007 Jul 15;17(14):4006-11. | |
BMS 433796 is a γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer's disease.
BMS-433796 cause a concentration-dependent decrease in [3H]IN973 binding, with IC50 value of 1.2 nM, very similar to the IC50 values for inhibition of Aβ40 in human embryonic kidney cells overexpressing the Swedish mutation of APP of 0.8 nM, respectively, and for inhibition of Aβ42 of 0.4 nM, respectively[2].
BMS 433796 is characterized in pharmacokinetic studies in male Sprague-Dawley rats. Following a 10-min intravenous infusion at 2.3 μmol/kg in PEG-400, the total body clearance of 40 is 5.2±0.82 mL/min/kg (means±SEM; n=3), indicating low clearance. The apparent terminal elimination half-life is 4.6±0.48 h. Oral administration of a PEG-400 suspension at 35 μmol/kg shows an oral bioavailability of 31% with prolonged absorption. BMS 433796 has satisfactory metabolic stability in human liver microsomal preparations and is not an inhibitor of human CYPs (IC50>100 μM)[1]. Brain Aβ40 is reduced as a result of administering BMS-433796 in a dose-dependent manner, with ED50 value of 2.4 mg/kg, respectively[2].
[1]. Prasad CV, et al. Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): a gamma-secretase inhibitor with Abeta lowering activity in a transgenic mouse model of Alzheimer's disease. Bioorg Med Chem Lett. 2007 Jul 15;17(14):4006-11. [2]. Goldstein ME, et al. Ex vivo occupancy of gamma-secretase inhibitors correlates with brain beta-amyloid peptide reduction in Tg2576 mice. J Pharmacol Exp Ther. 2007 Oct;323(1):102-8.
| Cas No. | 935525-13-6 | SDF | |
| 别名 | (ALPHAS)-N-[(1S)-2-[[(5S)-4,5-二氢-3-甲基-4-氧代-3H-2,3-苯并二氮杂卓-5-基]氨基]-1-甲基-2-氧代乙基]-3,5-二氟-ALPHA-羟基苯乙酰胺 | ||
| Canonical SMILES | O=C(N(C)N=CC1=C2C=CC=C1)[C@H]2NC(NC([C@@H](O)C3=CC(F)=CC(F)=C3)=O)=O | ||
| 分子式 | C19H16F2N4O4 | 分子量 | 402.35 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4854 mL | 12.427 mL | 24.854 mL |
| 5 mM | 0.4971 mL | 2.4854 mL | 4.9708 mL |
| 10 mM | 0.2485 mL | 1.2427 mL | 2.4854 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): a gamma-secretase inhibitor with Abeta lowering activity in a transgenic mouse model of Alzheimer's disease
We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.
Ex vivo occupancy of gamma-secretase inhibitors correlates with brain beta-amyloid peptide reduction in Tg2576 mice
Reduction of brain beta-amyloid peptide (Abeta) synthesis by gamma-secretase inhibitors is a promising approach for the treatment of Alzheimer's disease. However, measurement of central pharmacodynamic effects in the Alzheimer's disease patient will be a challenge. Determination of drug occupancy may facilitate the analysis of efficacy of gamma-secretase inhibitors in a clinical setting. In this study, the relationship of gamma-secretase site occupancy and brain Abeta40 reduction by gamma-secretase inhibitors was examined in Tg2576 mice. [3H](2R,3S)-2-Isobutyl-N1-((S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-3-propylsuccinamide (IN973) was used as a gamma-secretase radioligand, since it has been shown to bind to gamma-secretase in rat, rhesus, and human brains with high affinity and specificity. We extended these findings by showing that [3H]IN973 bound to gamma-secretase in Tg2576 brains with an affinity, specificity, and regional localization very similar to the other species. To quantify gamma-secretase occupancy by gamma-secretase inhibitors, an ex vivo binding assay was developed using [3H]IN973 and frozen brain sections from drug-treated mice. Gamma-secretase occupancy and brain Abeta40 reduction were found to be highly correlated in animals dosed with either 2-[(1R)-1-[[4-chlorophenyl)-sulfonyl](2,5-difluorophenyl)amino] ethyl]-5-fluoro-benzenepropanoic acid (BMS-299897) or (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) over a wide range of doses and times postdose, with the exception of the earliest times postdose. This lag in Abeta40 response to gamma-secretase inhibition is probably related to the delayed clearance of previously produced Abeta40. The excellent correlation between brain Abeta40 and gamma-secretase occupancy suggests that a positron emission tomography ligand for gamma-secretase could be a valuable biomarker to determine whether gamma-secretase inhibitors bind to their target in humans.