LY2811376

製品コードS1528 バッチS152801

化学情報

	Synonyms	N/A	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₁₅H₁₄F₂N₄S
	分子量	320.36	CAS No.	1194044-20-6
Solubility (25°C)*	体外	Ethanol	64 mg/mL (199.77 mM)
		DMSO	16 mg/mL (49.94 mM)
		Water	Insoluble
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	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.
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 APP^V717F mouse model of Aβ pathology. After treatment with LY2811376 (5 mg/kg), reductions in Aβ_1-x are observed in plasma, with a maximal 85% reduction observed from 4 to 12 h after dosing in beagle dogs. ^[1]
特徴	Approximately 10-fold selectivity toward BACE1 over BACE2.

プロトコル(参考用のみ)

キナーゼアッセイ	Determination of enzymatic efﬁciency
キナーゼアッセイ	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.
細胞アッセイ	細胞株	APP-overexpressing HEK293.
	濃度	~ 100 μM
	反応時間	48–72 hours
	実験の流れ	The cytotoxicity in the HEK293Swe cell model is assessed using a CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay.
動物実験	動物モデル	PDAPP transgenic mice.
	投薬量	10, 30, and 100 mg/kg doses
	投与方法	P.O.

参考

カスタマーフィードバック

: Data from [Neurobiol Aging, 2014, 35(7), 1570-81]

: Data from [Data independently produced by J Biol Chem, 2014, 289(30), 20871-8]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Interplay between APP and glypican-1 processing and α-synuclein aggregation in undifferentiated and differentiated human neural progenitor cells [ Glycobiology, 2023, 33(4):325-341]	PubMed: 36790131
Tangeretin Inhibits BACE1 Activity and Attenuates Cognitive Impairments in AD Model Mice [ J Agric Food Chem, 2022, 70(5):1536-1546]	PubMed: 35084179
Establishment and characterization of immortalized sweat gland myoepithelial cells [ Sci Rep, 2022, 12(1):7]	PubMed: 34997030
A study of protein-drug interaction based on solvent-induced protein aggregation by fluorescence correlation spectroscopy [ Analyst, 2022, 10.1039/d2an00031h]	PubMed: 35253833
Amyloidogenic Processing of Alzheimer's Disease β-amyloid Precursor Protein Induces Cellular Iron Retention [ Mol Psychiatry, 2020, 10.1038/s41380-020-0762-0]	PubMed: 32444869
A novel human colon signet-ring cell carcinoma organoid line: establishment, characterization and application [ Carcinogenesis, 2020, 41(7):993-1004]	PubMed: 31740922
Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half-life. [ Alzheimers Dement, 2019, 15(9):1183-1194]	PubMed: 31416794
A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor. [ J Cell Biol, 2019, 218(2):644-663]	PubMed: 30626721
Elevated cleavage of neuregulin-1 by beta-secretase 1 in plasma of schizophrenia patients. [ Prog Neuropsychopharmacol Biol Psychiatry, 2019, 90:161-168]	PubMed: 30500411
Neuregulin 3 Signaling Mediates Nicotine-Dependent Synaptic Plasticity in the Orbitofrontal Cortex and Cognition. [ Neuropsychopharmacology, 2018, 43(6):1343-1354]	PubMed: 29114105

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人間や獣医の診断であるか治療的な使用のためにでない。

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