Home Proteases BACE inhibitor - Beta Amyloid inhibitor LY2811376 For research use only.

LY2811376

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.

LY2811376 Chemical Structure

LY2811376 Chemical Structure

CAS No. 1194044-20-6

Purity & Quality Control

LY2811376 Related Products

Signaling Pathway

BACE Signaling Pathways

BACE Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
HEK293 cells Function assay Inhibition of BACE1 in HEK293 cells expressing APPswedish mutant assessed as inhibition of amyloid beta production by ELISA, EC50=0.3 μM 24704031
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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.
Features Approximately 10-fold selectivity toward BACE1 over BACE2.
Targets
BACE1 [1] Aβ [1]
239 nM-249 nM ~300 nM(EC50)
In vitro
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]
Kinase Assay Determination of enzymatic efficiency
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 final 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 efficiency (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 fitted 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.
Cell Research Cell lines APP-overexpressing HEK293.
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.
In Vivo
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 APPV717F mouse 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]
Animal Research Animal Models PDAPP transgenic mice.
Dosages 10, 30, and 100 mg/kg doses
Administration P.O.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00838084 Completed
Alzheimer''s Disease
Eli Lilly and Company
 December 2008 Phase 1

Chemical Information & Solubility

Molecular Weight 320.36 Formula

C15H14F2N4S
CAS No. 1194044-20-6 SDF Download LY2811376 SDF
Smiles CC1(CCSC(=N1)N)C2=C(C=C(C(=C2)C3=CN=CN=C3)F)F
Storage (From the date of receipt)

In vitro
Batch:

Ethanol : 64 mg/mL

DMSO : 16 mg/mL ( (49.94 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble


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In vivo
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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