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Purity: ≥98%
Semagacestat (also known as LY450139; LY4501) is a novel and potent γ-secretase inhibitor/blocker for Aβ42, Aβ40 and Aβ38 with the potential for treating Alzheimer's disease. In H4 human glioma cells, it inhibits Aβ42, Aβ40, and Aβ38 with IC50 values of 10.9 nM, 12.1 nM, and 12.0 nM.In addition, it inhibits Notch signaling with an IC50 of 14.1 nM. Due to a lackluster performance, semagacestat's Phase III trials were stopped in August 2010.
| Targets |
Aβ42 (IC50 = 10.9 nM); Aβ38 (IC50 = 12 nM); Aβ40 (IC50 = 12.1 nM); Notch (IC50 = 14.1 nM)
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| ln Vitro |
Semagacestat diminishes the amount of Aβ42, Aβ40, and Aβ38 secreted by H4 human glioma cells that persistently overexpress human wild-type APP into the culture medium (IC50 values of 10.9 nM, 12.1 nM, and 12.0 nM, respectively), all without impairing cell viability. Additionally, at high concentrations, semagacestat unexpectedly attenuates the increase in β-CTF in cell lysates, which has an ECmax of 16.0 nM. Semagacestat exhibits minimal selectivity in preserving Notch signaling, with Notch IC50/Aβ42 IC50 of only 1.3, and inhibits Notch signaling with an IC50 of 14.1 nM.[1] Semagacestat causes a concentration-dependent decrease in the amount of Aβ40 secreted into the medium, with an IC50 of 111 nM from murine CTX that expresses endogenous murine APP; however, based on data from neurons from wild type mice, the amount of murine Aβ42 formed in CTX is approximately 12-fold less than that of Aβ40.[2]
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| ln Vivo |
Using the Y-maze task, oral administration of Semagacestat (1 mg/kg) to 5.5-month-old APP-transgenic Tg2576 mice significantly improves memory deficits on spatial working memory. These effects vanish after 8 days of subchronic dosing. While LY450139 increases β-CTF at 0.3-10 mg/kg and decreases hippocampal levels of both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction) and 30 mg/kg (36-41% reduction), it does so in a dose-dependent manner with no inhibition on the processing of other γ-secretase substrates in the brain, such as Notch, N-cadherin, or EphA4. However, it impairs normal cognition in wild-type mice and 3-month-old Tg2576 mice, failing to restore cognitive deficits in the Y-maze test.[1]
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| Enzyme Assay |
Semagacestat is administered to H4 human glioma cells that are stable overexpressors of human wild-type APP695 for a duration of 24 hours at different concentrations. Using different ELISA kits, the levels of Aβ42, Aβ40, and Aβ38 in the media are measured. The constitutively active form of Notch (NotchΔE) expression vector is constructed into a pcDNA3.1 vector with a sequence modification from mouse to human, encoding bases 1-60 and 5193-6657 of the human Notch1 coding region (NM_017617). The Cignal RBP-Jk Reporter Assay Kit is used to assess notch signaling activity. The Notch intracellular domain produced by γ-secretase activates the transcription factor RBP-Jk protein [CSL/CBF1/Su(H)/Lag1]. The RBP-Jk-responsive luciferase construct and the human NotchΔE expression vector are transiently transfected into H4 cells using Lipofectamine 2000. The cells are then exposed to different concentrations of Semagacestat for a duration of 16 hours. The Dual-Glo Luciferase Assay System gauges notch signaling by measuring luciferase activity in the cell lysate.
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| Cell Assay |
Semagacestat is used to incubate cells for a full day. The ability of the cells to decrease 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) after being incubated with 0.5 mg/mL MTT for 60 minutes is used to determine the viability of the cells. Cells are digested and subjected to western blotting analysis in order to identify sAPP species.
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| Animal Protocol |
Mice: The Swedish mutation (K670N/M671L) in female Tg2576 mice expressing human APP695 is employed. It is necessary to obtain male transgenic mice and breed them with female B6SJLF1/J mice. Four distinct experiments are carried out to determine the effects of drugs on cognitive function. Experiment 1's goal is to clarify how acute and subchronic medication effects affect Tg2576 mice's cognitive deficits. Tg2576 mice, aged 5.5 months, are given oral doses of Semagacestat, BMS-708163, and GSM-2 for a duration of 8 days. Three hours after administration on days 1 and 8, Y-maze tests are used to assess spatial working memory. In the Y-maze test, vehicle-treated Tg2576 mice exhibit noticeably lower spontaneous alternation rates than WT mice, indicating impairments in spatial working memory. Acute effects of 1 mg/kg Semagacestat, 1 mg/kg BMS-708163, and 0.1–0.3 mg/kg GSM-2 are shown to significantly improve cognitive deficits on day 1. However, the GSI effects end on day 8, while the significant effects of GSM-2 (subchronic effects) are still present. On day 8, after the Y-maze test, mice are immediately killed so that ELISA can be used to measure the levels of Aβ42, Aβ40, and β-CTF in their hippocampi.
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| References |
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| Additional Infomation |
(2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide is a peptide.
Semagacestat has been used in trials studying the treatment of Alzheimer Disease. |
| Molecular Formula |
C19H27N3O4
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| Molecular Weight |
361.44
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| Exact Mass |
361.2
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| Elemental Analysis |
C, 63.14; H, 7.53; N, 11.63; O, 17.71
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| CAS # |
425386-60-3
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| Related CAS # |
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| PubChem CID |
9843750
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
681.9±55.0 °C at 760 mmHg
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| Melting Point |
208-212°C
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| Flash Point |
366.2±31.5 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.576
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| LogP |
2.23
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
537
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O=C1[C@]([H])(C2=C([H])C([H])=C([H])C([H])=C2C([H])([H])C([H])([H])N1C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])[H])N([H])C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])O[H])=O)=O
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| InChi Key |
PKXWXXPNHIWQHW-RCBQFDQVSA-N
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| InChi Code |
InChI=1S/C19H27N3O4/c1-11(2)16(23)18(25)20-12(3)17(24)21-15-14-8-6-5-7-13(14)9-10-22(4)19(15)26/h5-8,11-12,15-16,23H,9-10H2,1-4H3,(H,20,25)(H,21,24)/t12-,15-,16-/m0/s1
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| Chemical Name |
(2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide
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| Synonyms |
Semagacestat; LY450139; LY 4501; LY 450139; LY-450139; LY4501; LY-4501
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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 |
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| 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: ≥ 3 mg/mL (8.30 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 30.0 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: ≥ 3 mg/mL (8.30 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 3 mg/mL (8.30 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 0.5% methylcellulose: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7667 mL | 13.8336 mL | 27.6671 mL | |
| 5 mM | 0.5533 mL | 2.7667 mL | 5.5334 mL | |
| 10 mM | 0.2767 mL | 1.3834 mL | 2.7667 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01035138 | Completed | Drug: semagacestat | Alzheimer's Disease | Eli Lilly and Company | December 2009 | Phase 3 |
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