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LY2811376 1194044-20-6

Product Description

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Molecular Weight: 320.36 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 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.

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.

Protocol(Only for Reference)

Kinase Assay:


[2]

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 Assay:


[1]

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.





Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)


Species Baboon Dog Monkey Rabbit Guinea pig Rat Hamster Mouse
Weight (kg) 12 10 3 1.8 0.4 0.15 0.08 0.02
Body Surface Area (m2) 0.6 0.5 0.24 0.15 0.05 0.025 0.02 0.007
Km factor 20 20 12 12 8 6 5 3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by Animal B Km
Animal A Km



For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) × mouse Km(3) = 11.2 mg/kg
rat Km(6)







Chemical Information




Molecular Weight (MW) 320.36
Formula

C15H14F2N4S

CAS No. 1194044-20-6

Storage 3 years -20℃Powder
6 months-80℃in solvent (DMSO, water, etc.)
Synonyms



Solubility (25°C) * In vitro DMSO 16 mg/mL (49.94 mM)
Water <1 mg/mL (
Ethanol 64 mg/mL (199.77 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL





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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