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Daclatasvir (BMS-790052) HCV Protease inibitore

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

N. Cat.S1482

Daclatasvir (BMS-790052, EBP883) è un inibitore altamente selettivo di HCV NS5A con EC50 di 9-50 pM, per un'ampia gamma di genotipi di replicone di HCV e il virus infettivo JFH-1 genotipo 2a in coltura cellulare. Fase 3.

Daclatasvir (BMS-790052) HCV Protease inibitore Chemical Structure

Struttura chimica

Peso molecolare: 738.88

Vai a

Controllo Qualità

Lotto: Purezza: 99.70%

99.70

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

Coltura cellulare, trattamento e concentrazione di lavoro

Linee cellulari	Tipo di saggio	Concentrazione	Tempo di incubazione	Descrizione dellattività	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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Informazioni chimiche, conservazione e stabilità

Peso molecolare	738.88	Formula	C₄₀H₅₀N₈O₆	Conservazione (Dalla data di ricezione)	3 anni-20°Cpolvere
N. CAS	1009119-64-5	Scarica SDF		Conservazione delle soluzioni stock	1 anno-80°Cin solvente 1 mese-20°Cin solvente
Sinonimi	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

Solubilità

In vitro
Lotto:

DMSO : 148 mg/mL (200.3 mM)
(Il DMSO contaminato da umidità può ridurre la solubilità. Utilizzare DMSO fresco e anidro.)

Ethanol : 148 mg/mL

Water : Insoluble

Calcolatore di Molarità

Massa	Concentrazione	Volume	Peso molecolare
=	×	×

Calcolatore di Diluizione Calcolatore del Peso Molecolare

In vivo Lotto:
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.

Calcolatore di formulazione in vivo (Soluzione chiara)

Passo 1: Inserire le informazioni di seguito (Consigliato: Un animale aggiuntivo per tenere conto della perdita durante lesperimento)

Dosaggio: mg/kg Peso medio degli animali: g Volume di dosaggio per animale:μL Numero di animali:

Passo 2: Inserire la formulazione in vivo (Questo è solo il calcolatore, non la formulazione. Contattateci prima se non cè una formulazione in vivo nella sezione Solubilità.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Risultati del calcolo:

Concentrazione di lavoro: mg/ml;

Metodo per preparare il liquido master di DMSO: mg farmaco predissolto in μL DMSO ( Concentrazione del liquido master mg/mL, Vi preghiamo di contattarci prima se la concentrazione supera la solubilità del DMSO del lotto del farmaco. )

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungereμL PEG300, mescolare e chiarire, quindi aggiungereμL Tween 80, mescolare e chiarire, quindi aggiungere μL ddH₂O, mescolare e chiarire.

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungere μL Olio di mais, mescolare e chiarire.

Nota: 1. Si prega di assicurarsi che il liquido sia limpido prima di aggiungere il solvente successivo.
2. Assicurarsi di aggiungere il/i solvente/i in ordine. È necessario assicurarsi che la soluzione ottenuta, nellaggiunta precedente, sia una soluzione limpida prima di procedere allaggiunta del solvente successivo. Metodi fisici come il vortex, gli ultrasuoni o il bagno dacqua calda possono essere utilizzati per facilitare la dissoluzione.

Meccanismo dazione

Caratteristiche	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) è uno degli inibitori più potenti della replicazione dell'HCV riportati finora. I valori medi di EC50 di questo composto sono 50 e 9 pM per i repliconi di HCV genotipo 1a e 1b, rispettivamente. Mostra un indice terapeutico (CC50/EC50) di almeno 10⁵ ed è inattivo nei confronti di un panel di 10 virus a RNA e DNA, con EC50 superiori a 10 μM. Ciò conferma la sua specificità per l'HCV. Nelle cellule Huh7 che ospitano i repliconi di HCV genotipo 1b, blocca sia la replicazione transitoria che stabile del genoma dell'HCV, con valori di EC50 che vanno da 1-15 pM. A concentrazioni di 100 pM o 1 nM, è stato dimostrato che altera la localizzazione subcellulare e il frazionamento biochimico di NS5A. Questo composto inibisce i repliconi ibridi contenenti i geni NS5A del genotipo 4 dell'HCV con EC50 di 7-13 pM. Il residuo 30 di NS5A è un sito importante per la resistenza mediata da BMS-790052 nei repliconi ibridi.
Saggio chinasico	Saggio FRET per inibitori di HCV NS5A
Saggio chinasico	Questo peptide (Ac-Asp-Glu-Asp [EDANS]-Glu-Glu-Abu-[COO] Ala-Ser-Lys [DABCYL]-NH2) contiene un donatore fluorescente {EDANS, acido 5-[(2-amminoetil)ammino]naftalene-1-solfonico} vicino a un'estremità e un accettore {DABCYL, acido 4-[(4-dimetilammino)fenil]azo}benzoico} vicino all'altra estremità. Il trasferimento di energia di risonanza intermolecolare tra il donatore e l'accettore spegne la fluorescenza del peptide, ma quando la Protease NS3 scinde il peptide, i prodotti vengono rilasciati dallo spegnimento del trasferimento di energia di risonanza. La fluorescenza del donatore aumenta nel tempo man mano che più substrato viene scisso dalla Protease NS3. I reagenti di rilevamento sono: reagente di lisi di coltura cellulare di luciferasi 5× diluito con dH₂O a 1×, con aggiunta di NaCl (150 mM) e peptide FRET (20 μM). Le cellule HCV-Huh-7 sono state poste in piastre a 96 pozzetti e lasciate aderire durante la notte (1×10⁴ cellule per pozzetto). Il giorno successivo, Daclatasvir (BMS-790052) è stato aggiunto ai pozzetti e le piastre sono state incubate per 72 ore. Le piastre sono state quindi risciacquate con PBS e il saggio FRET è stato eseguito aggiungendo 30 μL del suddetto reagente di rilevamento del peptide FRET a ciascun pozzetto. I segnali sono stati acquisiti utilizzando uno strumento Cytofluor 4000, impostato in modalità automatica a 340 nm (eccitazione)/490 nm (emissione), eseguito per 20 cicli o meno, e leggendo le piastre in modalità cinetica. Dopo il saggio FRET, sono stati aggiunti 40 μL di substrato di luciferasi a ciascun pozzetto e l'attività della luciferasi è stata misurata.
Riferimenti	[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/

Informazioni sullo studio clinico

(dati da https://clinicaltrials.gov, aggiornato il 2024-05-22)

Numero NCT	Reclutamento	Condizioni	Sponsor/Collaboratori	Data di inizio	Fasi
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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