Home Proteases BACE inhibitor LY2811376

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LY2811376 BACE inhibitor

Cat.No.S1528

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 BACE inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 320.36

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Quality Control

Batch: Purity: 99.99%
99.99

Cell Culture, Treatment & Working Concentration

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
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Solubility

In vitro
Batch:

Ethanol : 64 mg/mL

DMSO : 16 mg/mL (49.94 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

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In vivo
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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Chemical Information, Storage & Stability

Molecular Weight 320.36 Formula

C15H14F2N4S

 Storage (From the date of receipt)
CAS No. 1194044-20-6 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CC1(CCSC(=N1)N)C2=C(C=C(C(=C2)C3=CN=CN=C3)F)F

Mechanism of Action

Features
Approximately 10-fold selectivity toward BACE1 over BACE2.
Targets/IC50/Ki
BACE1
239 nM-249 nM
Aβ
~300 nM(EC50)
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. This compound treatment yields a concentration-dependent decrease in Aβ secretion in APP-overexpressing HEK293 cells. It inhibits Aβ secretion with EC50 of ~100 nM in primary neuronal cultures of PDAPP transgenic mouse.
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.
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 this compound (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.
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00838084 Completed
Alzheimer''s Disease
Eli Lilly and Company
 December 2008 Phase 1

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