LY-411575

Gamma secretase inhibitor CAS# 209984-57-6

LY-411575

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Quality Control of LY-411575

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Chemical structure

LY-411575

3D structure

Chemical Properties of LY-411575

Cas No. 209984-57-6 SDF Download SDF
PubChem ID 10435235 Appearance Powder
Formula C26H23F2N3O4 M.Wt 479.48
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 33.33 mg/mL (69.51 mM; Need ultrasonic)
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
SMILES CC(C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3N(C1=O)C)NC(=O)C(C4=CC(=CC(=C4)F)F)O
Standard InChIKey ULSSJYNJIZWPSB-CVRXJBIPSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of LY-411575

DescriptionLY411575 is a potent γ-secretase inhibitor with IC50 value of 0.078 nM and 0.082 nM for membrane and cell-based, respectively.
Targetsγ-secretaseNotch S3 cleavage    
IC500.078 nM (membrane-based) 0.082 nM (cell-based)0.39 nM    

Protocol

Kinase experiment [1]:

Inhibitory activities

Procedures for measuring γ-secretase activity in membranes prepared from HEK293 cells expressing APP. Intact HEK293 cells expressing either APP or N E were treated with various concentrations of LY-411,575 for 4 h at 37℃. In the case of cells expressing N E, cells were lysed, the cell lysates were separated on a 4-12% NuPAGE gel, and the processed NICD fragment was detected via Western blot with a cleavage site-specific antibody. The inhibition of NICD production was quantified by spot densitometric analysis using FluorChem. In the case of cells expressing APP, the conditioned medium was collected, centrifuged at 10,000×g for 5 min to remove cell debris, and stored at -20℃ prior to the determination ofAβ levels. Aβ40 and -42 produced in HEK293 membrane- and cell-based assays, as well as plasma Aβ40 and cortex Aβ40 from TgCRND8 mice, were analyzed without pretreatment using an electrochemiluminescence detection-based immunoassay. Plasma Aβ42 was measured by enzyme-linked immunosorbent assay. A commercially available enzyme-linked immunosorbent assay kit was used to measure cortex Aβ42.

Cell experiment [1]:

Cell lines

HEK293 cells expressing human APP carrying both the Swedish and London mutations or N E.

Preparation method

Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

4 h.

Applications

In HEK293 cells expressing human APP or N E, LY-411,575 inhibits Aβ40 and NICD production with IC50 values of 0.082 and 0.39 nM, respectively.

Animal experiment [1]:

Animal models

Six-week-old female TgCRND8 or male C57BL/6 mice.

Dosage form

1-10 mg/kg; dosed orally once/day for 5 or 15 days.

Preparation method

Formulated as 10 mg/ml solutions in 50% polyethylene glycol, 30% propylene glycol, 10% ethanol and diluted in 0.4% methylcellulose for dosing.

Application

In TgCRND8 mice, LY-411,575 decreases brain and plasma Aβ40 and Aβ42. LY-411,575 (10 mg/kg) reduces weight of mice by 2 g. LY-411,575 induces a marked atrophy of the cortical zone of the thymus and reduces the amount of thymocyte cells.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem, 2004, 279(13): 12876-12882.

LY-411575 Dilution Calculator

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Preparing Stock Solutions of LY-411575

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0856 mL 10.428 mL 20.8559 mL 41.7119 mL 52.1398 mL
5 mM 0.4171 mL 2.0856 mL 4.1712 mL 8.3424 mL 10.428 mL
10 mM 0.2086 mL 1.0428 mL 2.0856 mL 4.1712 mL 5.214 mL
50 mM 0.0417 mL 0.2086 mL 0.4171 mL 0.8342 mL 1.0428 mL
100 mM 0.0209 mL 0.1043 mL 0.2086 mL 0.4171 mL 0.5214 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on LY-411575

LY-411575 is a potent  inhibitor of γ-secretase with IC50 value of 0.078 nM in membrane assay.[1]
γ-Secertase is one of intramenbrane-cleaving aspartyl protease which cleaves many type-I membrane proteins and many of them have important biological functions. γ-Secretase is a multi-subunit protease and it contains presenilin, nicastrin, APH-1(Anterior Pharynx- defective 1) and PEN-2. Presenilin contains Asp258 and Asp385 embedded in the sixth and seventh transmembrane domain and forms the active site. The feature of being a membrane integrated protease complex makes it difficult to be purified as well as studying its mechanism.γ-secretase is responsible for the generation Aβfrom the amyloid precursor protein.γ-Secertase has been considered as an important drug target for Alzheimer's disease.γ-Secertase also is responsible for Notch processing which is related to cancer such as leukemia.[2]
LY-411,575 significantly inhibits theγ-secretase activity in vitro. LY-411,575 inhibits the production of Aβproduction with IC50 value of 0.078 nM in membrane-assay and 0.082 nM in cell-basedγ-secretase assays, respectively. LY-411,575 also affects the Notch pathway by inhibiting Notch S3 cleavage with IC50 value of 0.39 nM.[1] LY-411,575 treatment also significantly inhibited the Notch pathway by inhibiting the γ-secretase activity luciferase activity in primary KS cells. LY-411,575 also induced the apoptosis though Notch pathway inhibition in primary and immortalized Kaposi's sarcoma (KS) tumor cells.[2]
LY-411,575 decreases the levels of brain and plasma Aβ40 and -42 at 10 mg/kg oral doses.[1] LY-411,575 also decreases cortical Aβ40 levels in transgenic CRND8 mice with ED50 ≈ 0.6 mg/kg. LY-411,575 also induced significantly intestinal goblet cell hyperplasia and thymus atrophy by inhibiting Notch signaling pathway at higher doses in vivo.[3]
References:
1.Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ et al: Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004, 279(13):12876-12882.
2.Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE: Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene 2005, 24(42):6333-6344.
3.Hyde LA, McHugh NA, Chen J, Zhang Q, Manfra D, Nomeir AA, Josien H, Bara T, Clader JW, Zhang L et al: Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-di hydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse. J Pharmacol Exp Ther 2006, 319(3):1133-1143.

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References on LY-411575

Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-di hydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575).[Pubmed:14718585]

J Pharmacol Exp Ther. 2004 Apr;309(1):49-55.

A previous study by us suggests the utility of cerebrospinal fluid (CSF) and plasma Abeta as biomarkers of beta- or gamma-secretase inhibition. The present study characterized further Abeta pharmacodynamics in these tissues from Tg2576 mice and examined their correlation with brain Abeta after acute treatment with a potent gamma-secretase inhibitor, N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6, 7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY-411575). A single dose of LY-411575 dose-dependently (0.1-10 mg/kg p.o.) reduced Abeta(1-40) and Abeta(1-42) in the CSF and the brain. In contrast, plasma Abeta levels were increased by 0.1 mg/kg LY-411575 and were followed by a dose-dependent reduction at higher doses. The time courses of Abeta reduction and recovery were distinct for the three tissues: maximal declines in Abeta levels were evident by 3 h in the CSF and plasma but not until 9 h in the brain. A recovery in Abeta levels was underway in the CSF by 9 h and nearly completed by 24 h in all tissues. The differential time courses in the three compartments do not seem to be due to pharmacokinetic factors. Five days of twice-daily treatment with LY-411575 not only sustained the Abeta reductions in all tissues but also significantly augmented the efficacy in the brain and plasma. The increased efficacy occurred in the absence of compound accumulation and was consistent with the recovery rates in each compartment. Overall, Abeta in the CSF and not plasma seems to be a better biomarker of brain Abeta reduction; however, the time course of Abeta changes needs to be established in clinical studies.

Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-d ihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide].[Pubmed:15743924]

J Pharmacol Exp Ther. 2005 May;313(2):902-8.

The efficacy of gamma-secretase inhibitors in vivo has, to date, been generally assessed in transgenic mouse models expressing increased levels of amyloid-beta (Abeta) peptide thereby allowing the detection of changes in Abeta production. However, it is not clear whether the in vivo potency of gamma-secretase inhibitors is independent of the level of amyloid precursor protein expression. In other words, does a gamma-secretase inhibitor have the same effect in nontransgenic physiological animals versus transgenic overexpressing animals? In the present study, an immunoassay has been developed which can detect Abeta(40) in the rat brain, where concentrations are much lower than those seen in transgenic mice such as Tg2576 (c. 0.7 and 25 nM, respectively) and in cerebrospinal fluid (CSF, c. 0.3 nM). Using this immunoassay, the effects of the gamma-secretase inhibitor LY-411575 [N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6 ,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide] were assessed and robust dose-dependent reductions in rat brain and CSF Abeta(40) levels were observed with ID(50) values of 1.3 mg/kg for both brain and CSF. These values were comparable with those calculated for LY-411575 in transgenic mice. Time course experiments using LY-411575 demonstrated comparable temporal reductions in rat brain and CSF Abeta(40), further suggesting these two pools of Abeta are related. Accordingly, when all the data for the dose-response curve and time course were correlated, a strong association was observed between the brain and CSF Abeta(40) levels. These data demonstrate the utility of the rat as a novel approach for assessing the effects of gamma-secretase inhibitors on central nervous system Abeta(40) levels in vivo.

Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575.[Pubmed:19419556]

Mol Neurodegener. 2009 May 6;4:19.

The gamma-secretase complex is a major therapeutic target for the prevention and treatment of Alzheimer's disease. Previous studies have shown that treatment of young APP mice with specific inhibitors of gamma-secretase prevented formation of new plaques. It has not yet been shown directly whether existing plaques would be affected by gamma-secretase inhibitor treatment. Similarly, alterations in neuronal morphology in the immediate vicinity of plaques represent a plaque-specific neurotoxic effect. Reversal of these alterations is an important endpoint of successful therapy whether or not a treatment affects plaque size. In the present study we used longitudinal imaging in vivo with multiphoton microscopy to study the effects of the orally active gamma-secretase inhibitor LY-411575 in 10-11 month old APP:PS1 mice with established amyloid pathology and neuritic abnormalities. Neurons expressed YFP allowing fluorescent detection of morphology whereas plaques were labelled with methoxy-XO4. The same identified neurites and plaques were followed in weekly imaging sessions in living mice treated daily (5 mg/kg) for 3 weeks with the compound. Although LY-411575 reduced Abeta levels in plasma and brain, it did not have an effect on the size of existing plaques. There was also no effect on the abnormal neuritic curvature near plaques, or the dystrophies in very close proximity to senile plaques. Our results suggest that therapeutics aimed at inhibition of Abeta generation are less effective for reversal of existing plaques than for prevention of new plaque formation and have no effect on the plaque-mediated neuritic abnormalities, at least under these conditions where Abeta production is suppressed but not completely blocked. Therefore, a combination therapy of Abeta suppression with agents that increase clearance of amyloid and/or prevent neurotoxicity might be needed for a more effective treatment in patients with pre-existing pathology.

Description

LY-411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), and also inhibits Notch S3 cleavage with IC50 of 0.39 nM.

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