Antibodies
LY2811376
- 貨號 Cat. No.
- S1528
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
LY2811376
Catalog No.S15281 Product Citations
LY2811376 is the first orally available non-peptidic β-secretase(BACE1) inhibitor with IC50 of 239 nM-249 nM, that act to decrease Aβ secretion with EC50 of 300 nM, demonstrated to have 10-fold selectivity towards BACE1 over BACE2, and more than 50-fold inhibition over other aspartic proteases including cathepsin D, pepsin, or renin. Phase 1.
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Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | LY2811376 is the first orally available non-peptidic β-secretase(BACE1) inhibitor with IC50 of 239 nM-249 nM, that act to decrease Aβ secretion with EC50 of 300 nM, demonstrated to have 10-fold selectivity towards BACE1 over BACE2, and more than 50-fold inhibition over other aspartic proteases including cathepsin D, pepsin, or renin. Phase 1. | |||||
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| Targets | BACE1 | Aβ | ||||
| IC50 | 239 nM/249 nM | ~300 nM (EC50) [1] | ||||
| In vitro | LY2811376 demonstrates concentration-dependent inhibition of hBACE1 with an IC50 of 239 and 249 nM against a small synthetic peptide or a larger chimeric protein substrate, respectively. LY2811376 treatment yields a concentration-dependent decrease in Aβ secretion in APP-overexpressing HEK293 cells. LY2811376 inhibits Aβ secretion with EC50 of ~100 nM in primary neuronal cultures of PDAPP transgenic mouse. [1] | |||||
| In vivo | Administration of LY2811376 (10, 30, and 100 mg/kg doses) results in dose-dependent, significant reductions in Aβ, as well as sAPPβ and C99, the proximal cleavage products of APP proteolysis by BACE1 in APPV717Fmouse model of Aβ pathology. After treatment with LY2811376 (5 mg/kg), reductions in Aβ1-x are observed in plasma, with a maximal 85% reduction observed from 4 to 12 h after dosing in beagle dogs. [1] | |||||
| Features | Approximately 10-fold selectivity toward BACE1 over BACE2. | |||||
Protocol(Only for Reference)
Kinase Assay:
| Determination of enzymatic efï¬ciency | The stock solution for each FRET peptide substrate is prepared at 30 mM in dimethylsulfoxide (DMSO). The huBACE1:Fc muBACE1:Fc preparation is concentrated through YM10 Centricon. to a ï¬nal concentration of at least 7 mg/mL. The optimal enzyme concentration for each FRET peptide substrate is determined individually at 30μM FRET peptide substrate in 50 mM ammonium acetate, pH 4.6, 1 mg/mL BSA and 1 mM Triton X-100. The enzymatic efï¬ciency (kcat /Km) of either of the BACE1 orthologs toward individual FRET peptide substrates at 15, 30 and 100μM is determined under the optimal conditions for each substrate. The progress of the reaction is monitored by measuring an increase of the emission signal at 420 nm with excitation wavelength set at 320 nm, using a GEMINI fluorescence plate reader. Amino acid conjugated aminobenzoate is used to convert the emission signal in the relative fluorescence units into the molar concentration of product generated in the reaction mixture. The initial phase of the timedependence curve is ï¬tted with a linear function whose slope is used to calculate the initial rate for huBACE1:Fc toward each peptide substrate. The kcat /Km values are calculated from the linear dependence of the initial rate on the concentration of each peptide. |
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Cell Assay:
| Cell lines | APP-overexpressing HEK293. |
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| Concentrations | ~ 100 μM |
| Incubation Time | 48–72 hours |
| Method | The cytotoxicity in the HEK293Swe cell model is assessed using a CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay. |
Animal Study:
| Animal Models | PDAPP transgenic mice. |
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| Dosages | 10, 30, and 100 mg/kg doses |
| Administration | P.O. |
| Solubility | 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL |
1
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00838084 | Completed | Alzheimer’s Disease | Eli Lilly and Company | 2008-12 | Phase 1 |
Chemical Information
Download LY2811376 SDF
| Molecular Weight (MW) | 320.36 |
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| Formula | C15H14F2N4S |
| CAS No. | 1194044-20-6 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | LY 2811376 |
| Solubility (25°C) * | In vitro | DMSO | 16 mg/mL (49 mM) |
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| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | 64 mg/mL (199 mM) | ||
| In vivo | 30% PEG400/0.5% Tween80/5% propylene glycol, | 30 mg/mL | |
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| Chemical Name | (S)-4-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine |
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Preparing Stock Solutions
| Stock Solution (1ml DMSO) | 1mM | 10mM | 20mM | 30mM |
|---|---|---|---|---|
| Mass(mg) | 0.32036 | 3.2036 | 6.4072 | 9.6108 |
Product Citations (1)
