BMS 433796 is a novel and potent γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer's disease. BMS-433796 exhibited favorable pharmacodynamic and pharmacokinetic profiles. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses. Reduction of brain beta-amyloid peptide (Abeta) synthesis by gamma-secretase inhibitors is a promising approach for the treatment of Alzheimer's disease.
Physicochemical Properties
| Molecular Formula | C19H16N4O4F2 |
| Molecular Weight | 402.35154 |
| Exact Mass | 402.114 |
| CAS # | 935525-13-6 |
| PubChem CID | 23656215 |
| Appearance | Typically exists as solid at room temperature |
| LogP | 1.789 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 31 |
| Complexity | 712 |
| Defined Atom Stereocenter Count | 3 |
| 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 |
| InChi Key | HXEHCCYOTHDPPI-NBHSMZAVSA-N |
| InChi Code | InChI=1S/C21H20F2N4O4/c1-11(25-20(30)18(28)13-7-14(22)9-15(23)8-13)19(29)26-17-16-6-4-3-5-12(16)10-24-27(2)21(17)31/h3-11,17-18,28H,1-2H3,(H,25,30)(H,26,29)/t11-,17-,18-/m0/s1 |
| Chemical Name | (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide |
| Synonyms | BMS433796; BMS-433796; BMS 433796. |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | At 1.2 nM, BMS-433796 reduced [3H]IN973 binding in a concentration-dependent manner. This value was comparable to the 0.8 nM inhibitory IC50 value of Aβ40 and the 0.8 nM inhibition of Aβ42 in human embryonic kidney cells overexpressing the Swedish mutant APP. 0.4 nanometers[2]. |
| ln Vivo | In a pharmacokinetic investigation using male Sprague-Dawley rats, BMS 433796 was described. The total clearance of 40 was 5.2 ± 0.82 mL/min/kg (mean ± SEM; n = 3), showing decreased clearance, after a 10-minute intravenous infusion of PEG-400 at 2.3 μmol/kg. It appears that the half-life of terminal elimination is 4.6±0.48 hours. With a lengthy absorption period, the oral bioavailability of the 35 μmol/kg PEG-400 solution is 31%. BMS 433796 is not an inhibitor of human CYP (IC50>100 μM) and exhibits acceptable metabolic stability in human liver microsomal preparations [1]. Following administration of BMS-433796, there was a dose-dependent reduction in brain Aβ40, with an ED50 of 2.4 mg/kg [2]. |
| References |
[1]. 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. [2]. 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. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4854 mL | 12.4270 mL | 24.8540 mL | |
| 5 mM | 0.4971 mL | 2.4854 mL | 4.9708 mL | |
| 10 mM | 0.2485 mL | 1.2427 mL | 2.4854 mL |