AZD1080 612487-72-6

.cp_wz tabla {borde superior: 1px sólido #ccc; borde izquierdo: 1px sólido #ccc; } .cp_wz table td {borde derecho: 1px sólido #ccc; borde inferior: 1px sólido #ccc; padding: 5px 0px 0px 5px;} .cp_wz table th {border-right: 1px solid #ccc; border-bottom: 1px solid #ccc; relleno: 5px 0px 0px 5px;} \ n Peso molecular: 334,37 AZD1080 es un inhibidor selectivo de GSK3 permeable al cerebro, activo por vía oral, inhibe GSK3α y GSK3β humanas con Ki de 6,9 ​​nM y 31 nM, respectivamente, muestra> 14 veces más selectividad contra CDK2, CDK5, CDK1 y Erk2. \ N AZD1080 es un inhibidor selectivo de GSK3 permeable al cerebro, activo por vía oral, inhibe GSK3α y GSK3β humanas con una Ki de 6,9 ​​nM y 31 nM, respectivamente, muestra una selectividad> 14 veces contra cdk2, cdk5 , cdk1 y Erk2. AZD1080 inhibe la fosforilación de tau en células que expresan tau humana, con IC50 de 324 nM. \ n AZD1080 inhibe la fosforilación de tau en el cerebro de rata después de la administración oral, con una relación de exposición cerebro / plasma de 0,5 a 0,8 a concentraciones máximas. AZD1080 revierte los déficits cognitivos y rescata las sinapsis disfuncionales en ratones. El tratamiento oral agudo con AZD1080 inhibe la actividad periférica de GSK3, produce una reducción dependiente de la dosis de la proporción de glucógeno sintasa (GS) fosforilada a total, con un efecto inhibidor máximo medio del 49% a la dosis más alta (10 μmol / kg) a las 2 h después de la dosificación. Un inhibidor de GSK3 permeable al cerebro.
orte

Kinase Assay

GSK3 scintillation proximity assay is done. The competition experiments are carried out in duplicate with 10 concentrations of the inhibitor in clear-bottomed microtiter plates. The biotinylated peptide substrate biotin-AAEELDSRAGS(PO3H2)PQL, is added at a final concentration of 2 μM in an assay buffer containing 6 milliunits of recombinant human GSK3 (equal mix of both α and β), 12 mM MOPS, pH 7.0, 0.3 mM EDTA, 0.01% β-mercaptoethanol, 0.004% Brij 35, 0.5% glycerol, and 0.5 μg of bovine serum albumin/25 μl and preincubated for 10–15 min. The reaction is initiated by the addition of 0.04 μCi of [γ-33P]ATP and unlabeled ATP in 50 mM Mg(Ac)2 to a final concentration of 1 μM ATP and assay volume of 25 μl. Blank controls without peptide substrate are used. After incubation for 20 min at room temperature, each reaction is terminated by the addition of 25 μl of stop solution containing 5 mM EDTA, 50 μM ATP, 0.1% Triton X-100, and 0.25 mg of streptavidin-coated SPA beads corresponding to 35 pmol of binding capacity. After 6 h the radioactivity is determined in a liquid scintillation counter.

Ensayo celular: [1]

Cell lines	3T3 fibroblasts stably expressing 4-repeat human tau
Concentrations	~20mM
Incubation Time	0-8 h
Method	3T3 fibroblasts are engineered to stably express four-repeat tau protein. These cells have high endogenous levels of GSK3 that is able to phosphorylate tau protein constitutively. This phosphorylation is inhibited by LiCl. After treatment with different compounds, cultures are washed twice with 5 mM MgCl2-PBS. Extracts for Western blot analysis are prepared by homogenizing cells in ice-cold extraction buffer consisting of 20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM NaF, 1% Triton X-100, 1 mM sodium orthovanadate, 10 mM EDTA, and protease inhibitors (2 mM phenylmethylsulfonyl fluoride, 10 μg/ml aprotinin, 10 μg/ml leupeptin, and 10 μg/ml pepstatin). The samples are homogenized at 4 °C, and protein content is determined by Bradford method. Total protein (25 μg) is electrophoresed on 10% SDS-PAGE gel and transferred to a nitrocellulose membrane. The experiments are performed using the following primary antibodies: tau Ser(P)-396, 1:1000; Tau5, 1:1000; and anti-GSK3β, 1:1000. The filters are incubated with the antibody at 4 °C overnight in 5% nonfat dried milk. A secondary antibody (1:5000), followed by ECL detection reagents are used for immunodetection. Quantitation of immunoreactivity is performed by densitometric scanning.

Estudio con animales: [1]

Animal Models	C57BL/6 mice
Formulation	water with 0.5% ascorbic acid, 0.01% EDTA, pH 2.0
Dosages	3 or 10 μmol/kg, 6 mL/kg
Administration	oral gavage
Solubility	30% PEG400/0.5% Tween80/5% propylene glycol, 20 mg/mL
* 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.

Conversión de diferentes modelos de animales basados ​​en BSA (valor basado en datos del Borrador de Directrices de la FDA)

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

Por ejemplo, para modificar la dosis de resveratrol utilizada para un ratón (22,4 mg / kg) a una dosis basada en el BSA para una rata, multiplique 22,4 mg / kg por el factor Km para un ratón y luego divida por el factor Km para una rata. Este cálculo da como resultado una dosis equivalente para ratas de resveratrol de 11,2 mg / kg.

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

\ n Información química

Molecular Weight (MW)	334.37
Formula	C19H18N4O2
CAS No.	612487-72-6

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

Solubility (25°C) *	In vitro	DMSO	52 mg/mL (155.51 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	30% PEG400/0.5% Tween80/5% propylene glycol	20 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	1H-Indole-5-carbonitrile, 2-hydroxy-3-[5-(4-morpholinylmethyl)-2-pyridinyl]-

Calculadora de molaridad Calculadora de dilución Calculadora de peso molecular

Grupos de Producto : PI3K / Akt / mTOR > Inhibidor GSK-3