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Purity: ≥98%
LY411575 (also named as LY-411575; LY 411575; LSN-411575; LSN411575) is a cell-permeable, selective, and dibenzoazepine-based gamma/γ-secretase inhibitor that may have anti-AD (Alzheimer's disease) properties. It also inhibits Notch cleavage in APP or NΔE-expressing HEK293 cells, with an IC50 of 0.39 nM, and γ-secretase, with an IC50 of 0.078 nM/0.082 nM (membrane/cell-based). LY 411575 can be used as an acute or long-term treatment to decrease the production of Aβ/42 and inhibit Notch activation, a pathway that controls cell proliferation and differentiation in a variety of adult tissues.
| Targets |
γ-secretase in membrane (IC50 = 0.078 nM); γ-secretase cell-based (IC50 = 0.082 nM); Notch S3 cleavage cell-based (IC50 = 0.39 nM)
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| ln Vitro |
LY-411575 inhibits γ-secretase, which is measured by substrates such as cleavage of Notch S3 and amyloid precursor protein (APP). Primarily, LY-411575 causes KS cells to undergo apoptosis by inhibiting Notch activation.[/2]
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| ln Vivo |
Oral LY-411575 dose of 10 mg/kg reduces brain and plasma Aβ40 and -42 in a dose-dependent manner.[1] In young (preplaque) transgenic CRND8 mice, LY-411575 lowers cortical Aβ40 (ED50 ≈ 0.6 mg/kg). At higher doses (>3 mg/kg), it causes significant thymus atrophy and intestinal goblet cell hyperplasia. In both young and old CRND8 mice, the therapeutic window is comparable following oral and subcutaneous administration. Following a two-week washout period, the thymus and intestinal side effects are both reversible. After three weeks of treatment with 1 mg/kg LY411575, cortical Aβ40 is reduced by 69% without causing any intestinal side effects; however, there is a change in coat color that has not been reported before.[3]
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| Enzyme Assay |
Methods for assessing γ-secretase activity in membranes made from APP-expressing HEK293 cells have been previously published (Zhang L et al Biochemistry 40, 5049-5055). LY-411,575 at different concentrations is applied to intact HEK293 cells that express either APP or NΔE for four hours at 37 °C. When it comes to cells that express NΔE, they are lysed, their lysates separated on a 4-12% NuPAGE gel, and the processed NICD fragment is found using a cleavage site-specific antibody on a Western blot. NICD production inhibition is measured by spot densitometric analysis with FluorChem. Regarding APP-expressing cells, the conditioned medium is taken, centrifuged at 10,000 × g for 5 minutes to eliminate cell fragments, and then kept at -20 °C until the levels of Aβ are measured. Using an electrochemiluminescence detection-based immunoassay, Aβ40 and -42 generated in HEK293 membrane- and cell-based experiments, along with plasma Aβ40 and cortex Aβ40 from TgCRND8 mice, are examined without prior treatment. The assay known as enzyme-linked immunosorbent is used to measure plasma Aβ42. Following the manufacturer's instructions, cortical Aβ42 is measured using a commercially available enzyme-linked immunosorbent assay kit.
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| Cell Assay |
Standard procedures are followed when staining DNA/PI. In summary, permeabilization of 1 × 106 cells is carried out using 100% ethanol and 15% FBS. After washing, 10 mg/mL of RNAse is added and the cells are treated for 15 minutes at 37 °C. Before being analyzed by flow cytometry, the cells are treated with 5 mg/mL of PI and incubated for 1 hour at 4 °C. 10,000 cells are analyzed for each gated determination. Using the Immunotech Annexin V staining kit in accordance with the manufacturer's instructions, the results are verified. Similar results are obtained from at least three separate experiments.
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| Animal Protocol |
Mice in the aged cohort (16–26 months old) are either newly retired from breeding or have never participated in an experiment. Mice are kept in separate housing with a plastic igloo and nesting material before dosing starts and throughout the study. Two to four hours after their last dose, mice are sacrificed. LY411,575 and LY-D are prepared as 10 mg/mL solutions for oral administration and diluted 1:10 with 0.4% methycellulose. When administering subcutaneous doses, 20% hydroxyl-propyl-β-cyclodextrin is added to a 1:10 stock solution containing 10 mg/mL. Serial dilutions from the 1 mg/mL solution are prepared using the suitable 1:10 vehicle if needed. It takes 10 mL/kg of dosage. LY411,575 and LY-D are dosed once daily in all studies to try to maintain continuous γ-secretase inhibition, since inhibition of plasma Aβ is still significant 24 but not 48 hours after oral administration of 10 mg/kg of the drug.
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| References |
| Molecular Formula |
C26H23F2N3O4
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| Molecular Weight |
479.48
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| Exact Mass |
479.17
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| Elemental Analysis |
C, 65.13; H, 4.84; F, 7.92; N, 8.76; O, 13.35
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| CAS # |
209984-57-6
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| Related CAS # |
LY-411575 isomer 1;209984-58-7;LY-411575 (isomer 2);2070009-70-8;LY-411575 (isomer 3);2070009-28-6
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| Appearance |
Solid powder
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| SMILES |
C[C@@H](C(=O)N[C@H]1C2=CC=CC=C2C3=CC=CC=C3N(C1=O)C)NC(=O)[C@H](C4=CC(=CC(=C4)F)F)O
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| InChi Key |
ULSSJYNJIZWPSB-CVRXJBIPSA-N
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| InChi Code |
InChI=1S/C26H23F2N3O4/c1-14(29-25(34)23(32)15-11-16(27)13-17(28)12-15)24(33)30-22-20-9-4-3-7-18(20)19-8-5-6-10-21(19)31(2)26(22)35/h3-14,22-23,32H,1-2H3,(H,29,34)(H,30,33)/t14-,22-,23-/m0/s1
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| Chemical Name |
(2S)-2-[[(2S)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-N-[(7S)-5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl]propanamide
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| Synonyms |
LSN-411575; LY 411575; LSN-411575; LY-411575; LY411575; LSN411575; LSN 411575
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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 |
| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0856 mL | 10.4280 mL | 20.8559 mL | |
| 5 mM | 0.4171 mL | 2.0856 mL | 4.1712 mL | |
| 10 mM | 0.2086 mL | 1.0428 mL | 2.0856 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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