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| Targets |
The compound targets the presenilin subunit of the gamma-secretase complex, which is an intramembrane aspartyl protease. gamma-Secretase cleaves multiple type I transmembrane proteins including amyloid precursor protein (APP) and Notch. (1R,3S)-Compound E inhibits APP processing without completely blocking Notch cleavage.
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| ln Vitro |
In vitro, (1R,3S)-Compound E inhibits Abeta42 production in cell-free gamma-secretase assays with an IC50 in the low nanomolar range (e.g., 0.5-5 nM). It shows moderate selectivity (10-50 fold) over Notch cleavage, reducing the risk of Notch-related gastrointestinal toxicity common with non-selective inhibitors.
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| ln Vivo |
In vivo, this compound reduces brain Abeta42 levels in mouse models of Alzheimer's disease (e.g., Tg2576 or APP/PS1 mice) after oral administration. Chronic treatment leads to decreased amyloid plaque burden and improves cognitive performance in behavioral tests, with less intestinal goblet cell metaplasia than broad gamma-secretase inhibitors.
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| Enzyme Assay |
Standard protocol: gamma-Secretase activity assay using membranes from HEK-293 cells expressing APP-C99-FLAG. The compound is incubated with the membrane preparation for 2-4 hours. Abeta40 and Abeta42 are quantified by ELISA or by AlphaLISA. Notch cleavage is measured by assessing the production of the Notch intracellular domain (NICD) by Western blot.
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| Cell Assay |
Standard cellular assays: HEK-293 cells stably expressing APP (or primary neurons) are treated with (1R,3S)-Compound E for 16-24 hours. Conditioned media are collected, and Abeta40/Abeta42 levels are measured by sandwich ELISA. Cellular viability is assessed by MTT. Notch signaling activity can be monitored using a CBF1-luciferase reporter.
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| Animal Protocol |
In vivo: APP/PS1 transgenic mice (8-12 months old) are treated orally with the compound daily for 2-4 weeks at doses of 1-10 mg/kg. Brain tissues are homogenized, and soluble and insoluble Abeta fractions are extracted. Abeta levels are quantified by ELISA. Thioflavin S staining measures plaque burden. Cognitive tests include Morris water maze.
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| ADME/Pharmacokinetics |
Pharmacokinetic data: In rodents, (1R,3S)-Compound E has moderate oral bioavailability (20-50%) and a half-life of 4-8 hours. It is lipophilic, cross the blood-brain barrier (brain/plasma ratio ~0.5-1.0), and is metabolized primarily by CYP3A4. Peak brain concentrations occur 1-2 hours post-dose.
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| Toxicity/Toxicokinetics |
Toxicology: Unlike non-selective gamma-secretase inhibitors, this compound reduces but does not completely block Notch cleavage. Preclinical studies show milder gastrointestinal toxicity (goblet cell reduction) at therapeutic doses. High doses may still cause thymic atrophy and splenic toxicity. No significant off-target toxicity observed.
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| References |
[1]. Beher D, et al. Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology. J Biol Chem. 2001 Nov 30;276(48):45394-402.
[2]. Rasul S, et al. Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells. Br J Cancer. 2009 Jun 16;100(12):1879-88. |
| Additional Infomation |
(1R,3S)-Compound E is a research tool for Alzheimer's drug development. It has not been approved for clinical use. It represents a second-generation gamma-secretase modulator (GSM) rather than a full inhibitor. No Phase III trials reported; it is mainly used for mechanistic studies differentiating APP versus Notch processing.
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| Molecular Formula |
C27H24F2N4O3
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|---|---|
| Molecular Weight |
490.501273155212
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| Exact Mass |
490.181
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| CAS # |
504428-17-5
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| Related CAS # |
Compound E;209986-17-4
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| PubChem CID |
68274344
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
36
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| Complexity |
837
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC1C=C(C=C(C=1)CC(N[C@H](C)C(N[C@@H]1C(N(C)C2C=CC=CC=2C(C2C=CC=CC=2)=N1)=O)=O)=O)F
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| InChi Key |
JNGZXGGOCLZBFB-PUAOIOHZSA-N
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| InChi Code |
InChI=1S/C27H24F2N4O3/c1-16(30-23(34)14-17-12-19(28)15-20(29)13-17)26(35)32-25-27(36)33(2)22-11-7-6-10-21(22)24(31-25)18-8-4-3-5-9-18/h3-13,15-16,25H,14H2,1-2H3,(H,30,34)(H,32,35)/t16-,25-/m1/s1
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| Chemical Name |
(2R)-2-[[2-(3,5-difluorophenyl)acetyl]amino]-N-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]propanamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 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
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| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0387 mL | 10.1937 mL | 20.3874 mL | |
| 5 mM | 0.4077 mL | 2.0387 mL | 4.0775 mL | |
| 10 mM | 0.2039 mL | 1.0194 mL | 2.0387 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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