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Daclatasvir (BMS-790052) HCV Protease inhibidor

Name: Daclatasvir (BMS-790052)
Brand: Selleck Chemicals
SKU: S1482
Rating: 5 (56 reviews)

Cat. No.S1482

Daclatasvir (BMS-790052, EBP883) es un inhibidor altamente selectivo de HCV NS5A con una EC50 de 9-50 pM, para un amplio rango de genotipos de replicón de VHC y el virus infeccioso JFH-1 genotipo 2a en cultivo celular. Fase 3.

Daclatasvir (BMS-790052) HCV Protease inhibidor Chemical Structure

Estructura química

Peso molecular: 738.88

Saltar a

Control de calidad

Lote: Pureza: 99.70%

99.70

Dianas relacionadas	HDAC Caspase Proteasome Secretase MMP Cysteine Protease DPP Tyrosinase HIV Protease Serine Protease
Otros HCV Protease Inhibidores	Danoprevir Lomibuvir (VX-222) Asunaprevir Tizoxanide PSI-6206 (GS-331007) Mecarbinate Tegobuvir Herba taxilli Extract 2'-C-Methylcytidine

Cultivo celular, tratamiento y concentración de trabajo

Líneas celulares	Tipo de ensayo	Concentración	Tiempo de incubación	Descripción de la actividad	PMID
human CEM cells	Cytotoxicity assay		3 days	Cytotoxicity against human CEM cells after 3 days, CC50=9.6 μM	25154714
Huh7	Antiviral assay		3 days	Antiviral activity against HCV genotype 1b infected in human Huh7 cells after 3 days by cell-based replicon assay, EC50=0.000003μM	25148100
Huh-luc/neo-ET replicon	Antiviral assay		48 hrs	Antiviral activity against Hepatitis C virus genotype 1b harboring NS5A L28V mutant gene in Huh-luc/neo-ET replicon cells after 48 hrs by transient replicon mutant-based luciferase assay, EC50=0.000004μM	24568313
HuH7	Antiviral assay			Antiviral activity against HCV genotype 1b infected in human HuH7 cells assessed as reduction in viral RNA replication, EC50=0.000004μM	26099532
HuH7	Antiviral assay			Antiviral activity against HCV1b infected in human HuH7 cells assessed as inhibition of viral replication by RT-PCR analysis, EC50=0.0000066μM	22507961
HuH-Lcu-Neo	Function assay		48 hrs	Inhibition of NS5A in HCV genotype 1b infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay, EC50=0.0000081μM	32202782
Huh-5.2	Antiviral assay		4 days	Antiviral activity against Hepatitis C virus genotype 1b infected in human Huh-5.2 cells assessed as decrease in HCV replicon RNA replication after 4 days by luciferase assay, EC50=0.000009μM	24900811
HuH7	Antiviral assay		3 days	Antiviral activity against HCV genotype 1b Con1 infected in human HuH7 cells assessed as inhibition of viral RNA replication after 3 days by renilla luciferase reporter gene assay, EC50=0.000009μM	24320933
HuH7	Antiviral assay		72 hrs	Antiviral activity against HCV1b infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by FRET assay, EC50=0.000009μM	24521299
HuH7	Antiviral assay			Antiviral activity against HCV genotype 1b Con1 infected in human HuH7 cells assessed as inhibition of viral replication, EC50=0.000009μM	26077493
Huh7.5/J6/JFH1/EMCVIRES/hRlucNeo	Function assay		72 hrs	Inhibition of NS5A in HCV genotype 2a infected in human Huh7.5/J6/JFH1/EMCVIRES/hRlucNeo cells assessed as inhibition of replicon levels incubated for 72 hrs by luciferase reporter gene assay, IC50=0.000009μM	31710479
HuH7 replicon	Function assay		2 days	Inhibition of NS5A in HCV genotype 1b infected in human HuH7 replicon cells assessed as reduction in subgenomic viral RNA replication treated for 2 days followed by compound washout and subsequent compound dosing measured after 1 day by SEAP reporter gene, EC50=0.000009μM	30772607
HuH7	Antiviral assay			Antiviral activity against HCV 1b infected in human HuH7 cells by in vitro replicon assay, EC50=0.00001μM	23466233
Huh-luc/neo-ET replicon	Antiviral assay		48 hrs	Antiviral activity against Hepatitis C virus genotype 1b in Huh-luc/neo-ET replicon cells after 48 hrs by replicon-based luciferase assay, EC50=0.00001μM	24568313
HuH7	Function assay			Inhibition of NS5A in HCV genotype-1b infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.000023μM	25453810
HuH7.5/Con1/SG-Neo(I)-hRluc2aUb	Function assay		72 hrs	Inhibition of NS5A in HCV genotype 1b infected in human HuH7.5/Con1/SG-Neo(I)-hRluc2aUb cells assessed as inhibition of replicon levels incubated for 72 hrs by luciferase reporter gene assay, IC50=0.000023μM	31710479
HuH7	Antiviral assay			Antiviral activity against HCV genotype 1b JFH-1 infected in human HuH7 cells assessed as inhibition of viral replication, EC50=0.000028μM	26077493
HuH7	Antiviral assay			Antiviral activity against HCV 1b infected in human HuH7 cells by in vitro replicon assay, EC90=0.00003μM	23466233
HuH-Lcu-Neo	Function assay		48 hrs	Inhibition of NS5A in HCV genotype 1a infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay, EC50=0.0000324μM	32202782
HuH7	Antiviral assay			Antiviral activity against HCV genotype 1b expressing NS5A L31V mutant infected in human HuH7 cells assessed as reduction in viral RNA replication, EC50=0.000035μM	26099532
Huh-luc/neo-ET replicon	Antiviral assay		48 hrs	Antiviral activity against Hepatitis C virus genotype 1a in Huh-luc/neo-ET replicon cells after 48 hrs by replicon-based luciferase assay, EC50=0.0000398μM	24568313
HuH7	Antiviral assay			Antiviral activity against wild type HCV genotype 1b infected in human HuH7 cells assessed as reduction in viral RNA replication, EC50=0.000048μM	26099532
W11.8	Antiviral assay		4 days	Antiviral activity against Hepatitis C virus genotype 1a infected in W11.8 cells assessed as decrease in NS5A expression in replicon cell after 4 days by luminescence based ELISA, EC50=0.00005μM	24900811
HuH7	Antiviral assay		3 days	Antiviral activity against HCV genotype 1a H77 infected in human HuH7 cells assessed as inhibition of viral RNA replication after 3 days by renilla luciferase reporter gene assay, EC50=0.00005μM	24320933
HuH7	Antiviral assay		72 hrs	Antiviral activity against HCV1a infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by FRET assay, EC50=0.00005μM	24521299
HuH7	Antiviral assay			Antiviral activity against HCV genotype 5a infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.000051μM	25453811
HuH7	Antiviral assay			Antiviral activity against HCV genotype 1b infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.000073μM	25453811
HuH-Lcu-Neo	Function assay		48 hrs	Inhibition of NS5A in patient-derived HCV genotype 3a infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay, EC50=0.0001145μM	32202782
Huh-luc/neo-ET replicon	Antiviral assay		48 hrs	Antiviral activity against Hepatitis C virus genotype 1b harboring NS5A L31V mutant gene in Huh-luc/neo-ET replicon cells after 48 hrs by transient replicon mutant-based luciferase assay, EC50=0.0001259μM	24568313
HuH7	Function assay			Inhibition of NS5A in HCV genotype-1a infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.00014μM	25453810
HuH7	Antiviral assay			Antiviral activity against HCV genotype 1a infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.00014μM	25453811
HuH7	Antiviral assay			Antiviral activity against HCV genotype 1b expressing NS5A Y93H mutant infected in human HuH7 cells assessed as reduction in viral RNA replication, EC50=0.00018μM	26099532
Huh-luc/neo-ET replicon	Antiviral assay		48 hrs	Antiviral activity against Hepatitis C virus genotype 1b harboring NS5A Y93H mutant gene in Huh-luc/neo-ET replicon cells after 48 hrs by transient replicon mutant-based luciferase assay, EC50=0.0003162μM	24568313
HuH7	Antiviral assay		72 hrs	Antiviral activity against HCV1a infected in human HuH7 cells assessed as inhibition of viral replication after 72 hrs by FRET assay, EC90=0.00038μM	24521299
HuH7	Antiviral assay			Antiviral activity against HCV genotype 4a infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.00041μM	25453811
HuH-Lcu-Neo	Function assay		48 hrs	Inhibition of NS5A in HCV genotype 3a con infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay, EC50=0.0004115μM	32202782
HuH7	Antiviral assay			Antiviral activity against HCV genotype 6a infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.00045μM	25453811
HuH7	Antiviral assay			Antiviral activity against HCV genotype 3a infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.00067μM	25453811
HuH7	Antiviral assay			Antiviral activity against HCV genotype 2a infected in human HuH7 cells by luciferase reporter gene assay, EC50=0.00067μM	25453811
HuH-Lcu-Neo	Function assay		48 hrs	Inhibition of NS5A in patient-derived HCV genotype 2a infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay, EC50=0.0494μM	32202782
HuH-Lcu-Neo	Function assay		48 hrs	Inhibition of NS5A in HCV genotype 2a con infected in HuH-Lcu-Neo cells assessed as reduction in viral replication incubated for 48 hrs by luciferase reporter gene assay, EC50=0.05285μM	32202782
CEM	Cytotoxicity assay		3 days	Cytotoxicity against human CEM cells after 3 days, CC50=9.6μM	22507961
CEM	Cytotoxicity assay			Cytotoxicity against human CEM cells, CC50=9.6μM	22704887
Vero	Cytotoxicity assay			Cytotoxicity against african green monkey Vero cells, CC50=9.6μM	23466233
CEM	Cytotoxicity assay			Cytotoxicity against human CEM cells, CC50=10μM	26099532
PBMC	Cytotoxicity assay			Cytotoxicity against human PBMC cells, CC50=19μM	22704887
Vero	Cytotoxicity assay		3 days	Cytotoxicity against african green monkey Vero cells after 3 days, CC50=21μM	22507961
Vero	Cytotoxicity assay			Cytotoxicity against african green monkey Vero cells, CC50=21μM	22704887
CEM	Cytotoxicity assay			Cytotoxicity against human CEM cells, CC50=21μM	23466233
Vero	Cytotoxicity assay			Cytotoxicity against african green monkey Vero cells, CC50=21μM	26099532
Huh7.5.1	Antiviral assay	100 pM to 1 uM		Antiviral activity against HCV genotype 1b NK/R2AN infected in human Huh7.5.1 cells expressing NS5A L31V mutant assessed as reduction in virus replication at 100 pM to 1 uM by luciferase reporter gene assay	26134551
Huh7.5.1	Antiviral assay	100 pM to 1 uM		Antiviral activity against HCV genotype 1b NK/R2AN infected in human Huh7.5.1 cells expressing NS5A Y93H mutant assessed as reduction in virus replication at 100 pM to 1 uM by luciferase reporter gene assay	26134551
GS4.3	Antiviral assay	0.15 uM	6 days	Antiviral activity against HCV infected in human GS4.3 cells assessed as inhibition of NS3/4A levels at 0.15 uM treated with fresh media containing compound every 2 days measured after 6 days by Western blot method	29232582
GS4.3	Antiviral assay	0.15 uM	6 days	Antiviral activity against HCV infected in human GS4.3 cells assessed as inhibition of viral core protein levels at 0.15 uM treated with fresh media containing compound every 2 days measured after 6 days by Western blot method	29232582
HuH7	Antiviral assay		3 days	Antiviral activity against HCV genotype 1b infected in human HuH7 cells at >= 10 times antiviral EC50 after 3 days by luciferase reporter assay	28430437
HuH7	Antiviral assay		3 days	Antiviral activity against HCV genotype 1b infected in human HuH7 cells co-treated with asunaprevir after 3 days by luciferase reporter assay	28430437
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Información química, almacenamiento y estabilidad

Peso molecular	738.88	Fórmula	C₄₀H₅₀N₈O₆	Almacenamiento (Desde la fecha de recepción)	3 años-20°Cpolvo
Nº CAS	1009119-64-5	Descargar SDF		Almacenamiento de soluciones madre	1 año-80°Cen disolvente 1 mes-20°Cen disolvente
Sinónimos	EBP883			Smiles	CC(C)C(C(=O)N1CCCC1C2=NC=C(N2)C3=CC=C(C=C3)C4=CC=C(C=C4)C5=CN=C(N5)C6CCCN6C(=O)C(C(C)C)NC(=O)OC)NC(=O)OC

Solubilidad

In vitro
Lote:

DMSO : 148 mg/mL (200.3 mM)
(El DMSO contaminado con humedad puede reducir la solubilidad. Usar DMSO fresco y anhidro.)

Ethanol : 148 mg/mL

Water : Insoluble

Calculadora de Molaridad

Masa	Concentración	Volumen	Peso molecular
=	×	×

Calculadora de Dilución Calculadora de Peso Molecular

In vivo Lote:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

Calculadora de formulación in vivo (Solución clara)

Paso 1: Introduzca la información a continuación (Recomendado: Un animal adicional para tener en cuenta la pérdida durante el experimento)

Dosis: mg/kg Peso promedio de los animales: g Volumen de dosificación por animal:μL Número de animales:

Paso 2: Introduzca la formulación in vivo (Esto es solo la calculadora, no la formulación. Por favor, contáctenos primero si no hay una formulación in vivo en la sección de Solubilidad.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Resultados del cálculo:

Concentración de trabajo: mg/ml;

Método para preparar el líquido maestro de DMSO: mg fármaco predissuelto en μL DMSO ( Concentración del líquido maestro mg/mL, Por favor, contáctenos primero si la concentración excede la solubilidad del DMSO del lote del fármaco. )

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadirμL PEG300, mezclar y clarificar, luego añadirμL Tween 80, mezclar y clarificar, luego añadir μL ddH₂O, mezclar y clarificar.

Método para preparar la formulación in vivo: Tomar μL DMSO líquido maestro, luego añadir μL Aceite de maíz, mezclar y clarificar.

Nota: 1. Por favor, asegúrese de que el líquido esté claro antes de añadir el siguiente disolvente.
2. Asegúrese de añadir el (los) disolvente(s) en orden. Debe asegurarse de que la solución obtenida, en la adición anterior, sea una solución clara antes de proceder a añadir el siguiente disolvente. Se pueden utilizar métodos físicos como el vórtice, el ultrasonido o el baño de agua caliente para ayudar a la disolución.

Mecanismo de acción

Características	First-in-class, highly selective inhibitor of hepatitis C virus (HCV) NS5A with picomolar EC50 values.
Targets/IC₅₀/Ki	HCV NS5A 9 pM-50 pM(EC50)
In vitro	Daclatasvir (BMS-790052) es uno de los inhibidores más potentes de la replicación del VHC reportados hasta ahora. Los valores medios de EC50 de este compuesto son 50 y 9 pM para los replicones de VHC genotipo 1a y 1b, respectivamente. Muestra un índice terapéutico (CC50/EC50) de al menos 10⁵ y es inactivo frente a un panel de 10 virus de ARN y ADN, con una EC50 superior a 10 μM. Esto confirma su especificidad para el VHC. En células Huh7 que albergan los replicones de VHC genotipo 1b, bloquea la replicación del genoma del VHC, tanto transitoria como estable, con valores de EC50 que van de 1 a 15 pM. A concentraciones de 100 pM o 1 nM, se ha demostrado que altera la localización subcelular y el fraccionamiento bioquímico de NS5A. Este compuesto inhibe los replicones híbridos que contienen genes NS5A del genotipo 4 del VHC con una EC50 de 7-13 pM. El residuo 30 de NS5A es un sitio importante para la resistencia mediada por BMS-790052 en los replicones híbridos.
Ensayo de quinasa	Ensayo FRET para inhibidores de HCV NS5A
Ensayo de quinasa	Este péptido (Ac-Asp-Glu-Asp [EDANS]-Glu-Glu-Abu-[COO] Ala-Ser-Lys [DABCYL]-NH2) contiene un donante fluorescente {EDANS, ácido 5-[(2-aminoetil)amino]naftaleno-1-sulfónico} cerca de un extremo y un aceptor {DABCYL, ácido 4-[(4-dimetilamino)fenil]azo}benzoico} cerca del otro extremo. La transferencia de energía de resonancia intermolecular entre el donante y el aceptor extingue la fluorescencia del péptido, pero a medida que la Protease NS3 escinde el péptido, los productos se liberan de la extinción por transferencia de energía de resonancia. La fluorescencia del donante aumenta con el tiempo a medida que se escinde más sustrato por la Protease NS3. Los reactivos de detección son: reactivo de lisis de cultivo celular de luciferasa 5× diluido con dH₂O a 1×, con NaCl (150 mM) y péptido FRET (20 μM) añadidos. Las células HCV-Huh-7 se colocaron en placas de 96 pocillos y se dejaron adherir durante la noche (1×10⁴ células por pocillo). Al día siguiente, se añadió Daclatasvir (BMS-790052) a los pocillos y las placas se incubaron durante 72 horas. Luego, las placas se enjuagaron con PBS y se realizó el ensayo FRET añadiendo 30 μL del reactivo de detección del péptido FRET antes mencionado a cada pocillo. Las señales se adquirieron utilizando un instrumento Cytofluor 4000, configurado en modo automático de 340 nm (excitación)/490 nm (emisión), ejecutado durante 20 ciclos o menos, y leyendo las placas en modo cinético. Después del ensayo FRET, se añadieron 40 μL de sustrato de luciferasa a cada pocillo y se midió la actividad de la luciferasa.
Referencias	[1] https://pubmed.ncbi.nlm.nih.gov/20410884/ [2] https://pubmed.ncbi.nlm.nih.gov/21513964/ [3] https://pubmed.ncbi.nlm.nih.gov/22203595/ [4] https://pubmed.ncbi.nlm.nih.gov/15793110/

Información del ensayo clínico

(datos de https://clinicaltrials.gov, actualizado el 2024-05-22)

Número NCT	Reclutamiento	Condiciones	Patrocinador/Colaboradores	Fecha de inicio	Fases
NCT05992077	Recruiting	HCV Infection	ANRS Emerging Infectious Diseases	August 7 2023	Not Applicable
NCT04852614	Recruiting	Hepatitis C Virus Infection	Ain Shams University	December 1 2020	--
NCT04773756	Completed	Covid19	Alexandria University	November 1 2020	Phase 4
NCT03208322	Withdrawn	Hepatitis C	Bristol-Myers Squibb	November 30 2018	--

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