Dasabuvir
Descripción general
Descripción
Dasabuvir, vendido bajo la marca Exviera, es un medicamento antiviral utilizado para el tratamiento de la infección crónica por el virus de la hepatitis C (VHC). Es un inhibidor no nucleósido de la ARN polimerasa dependiente de ARN del VHC, que se dirige específicamente a la polimerasa NS5B . This compound se utiliza a menudo en combinación con otros agentes antivirales como ombitasvir, paritaprevir y ritonavir para lograr una respuesta virológica sostenida (RVS) en los pacientes .
Aplicaciones Científicas De Investigación
Dasabuvir tiene varias aplicaciones de investigación científica, incluyendo:
Mecanismo De Acción
Dasabuvir ejerce sus efectos antivirales inhibiendo la ARN polimerasa dependiente de ARN del VHC codificada por el gen NS5B. Se une al dominio de la palma de la polimerasa NS5B, induciendo un cambio conformacional que hace que la polimerasa no pueda alargar el ARN viral. Esta inhibición previene la replicación del genoma viral, lo que lleva a una reducción de la carga viral y finalmente a lograr una respuesta virológica sostenida .
Compuestos Similares:
Efavirenz: Otro inhibidor no nucleósido utilizado en el tratamiento de la infección por el VIH.
Tipranavir: Un inhibidor de la proteasa utilizado en combinación con otros agentes antirretrovirales para el tratamiento del VIH.
Comparación: this compound es único en su diana específica de la polimerasa NS5B del VHC, mientras que Efavirenz y Tipranavir se dirigen a diferentes enzimas virales. La alta especificidad de this compound para la polimerasa NS5B lo hace particularmente eficaz contra el genotipo 1 del VHC, mientras que Efavirenz y Tipranavir se utilizan para el tratamiento del VIH .
Análisis Bioquímico
Biochemical Properties
Dasabuvir plays a crucial role in inhibiting the replication of the Hepatitis C virus by targeting the NS5B RNA polymerase . This enzyme is responsible for the synthesis of viral RNA, and its inhibition prevents the virus from replicating. This compound binds to the polymerase at a site distinct from the active site, causing a conformational change that reduces the enzyme’s activity . This interaction is highly specific, and this compound does not significantly affect human RNA polymerases, making it a potent antiviral agent with minimal off-target effects .
Cellular Effects
This compound has significant effects on infected hepatocytes, the primary target cells of HCV . By inhibiting the NS5B RNA polymerase, this compound effectively halts viral replication within these cells. This leads to a reduction in viral load and allows the immune system to clear the infection . Additionally, this compound has been shown to influence cell signaling pathways involved in the antiviral response, enhancing the production of interferons and other antiviral cytokines . This helps to boost the overall immune response against the virus.
Molecular Mechanism
The molecular mechanism of this compound involves its binding to the NS5B RNA polymerase of HCV . This compound binds to an allosteric site on the polymerase, inducing a conformational change that inhibits the enzyme’s activity . This prevents the synthesis of viral RNA, effectively stopping the replication of the virus . The specificity of this compound for the HCV polymerase ensures that it does not interfere with human RNA polymerases, reducing the risk of side effects .
Temporal Effects in Laboratory Settings
In laboratory settings, this compound has been shown to be stable and effective over extended periods . Studies have demonstrated that this compound maintains its antiviral activity for several days in cell culture systems . Prolonged exposure to this compound can lead to the emergence of resistant viral strains, highlighting the importance of combination therapy to prevent resistance . The stability of this compound in various formulations also ensures its efficacy in clinical use .
Dosage Effects in Animal Models
In animal models, the effects of this compound vary with different dosages . At therapeutic doses, this compound effectively reduces viral load without causing significant toxicity . At higher doses, this compound can cause adverse effects such as hepatotoxicity and gastrointestinal disturbances . These findings underscore the importance of careful dose optimization in clinical settings to maximize efficacy while minimizing side effects .
Metabolic Pathways
This compound is metabolized primarily in the liver by the cytochrome P450 enzyme system, particularly CYP3A4 . This enzyme converts this compound into its inactive metabolites, which are then excreted via the bile and urine . The involvement of CYP3A4 in this compound metabolism means that drug interactions with other medications metabolized by this enzyme must be carefully managed to avoid adverse effects .
Transport and Distribution
Within cells, this compound is transported and distributed primarily in the cytoplasm, where it exerts its antiviral effects . This compound does not require active transport mechanisms to enter cells, as it can diffuse across cell membranes due to its lipophilic nature . Once inside the cell, this compound accumulates in the cytoplasm and binds to the NS5B RNA polymerase .
Subcellular Localization
This compound is predominantly localized in the cytoplasm of infected hepatocytes . This localization is crucial for its antiviral activity, as the NS5B RNA polymerase is also found in the cytoplasm . This compound does not undergo significant post-translational modifications or targeting to other cellular compartments, ensuring its specific action against the viral polymerase .
Métodos De Preparación
Rutas de Síntesis y Condiciones de Reacción: La síntesis de Dasabuvir implica múltiples pasos, comenzando con materiales de partida disponibles comercialmente. Los pasos clave incluyen la formación de la porción de metanosulfonamida y el acoplamiento de los grupos naftil y pirimidinil. Las condiciones de reacción normalmente implican el uso de disolventes orgánicos, catalizadores y temperaturas controladas para asegurar un alto rendimiento y pureza .
Métodos de Producción Industrial: La producción industrial de this compound sigue una ruta de síntesis similar pero se optimiza para la fabricación a gran escala. Esto incluye el uso de reactores de flujo continuo, sistemas automatizados y estrictas medidas de control de calidad para garantizar la coherencia y el cumplimiento de las normas reglamentarias .
Análisis De Reacciones Químicas
Tipos de Reacciones: Dasabuvir experimenta varias reacciones químicas, incluyendo:
Oxidación: this compound puede oxidarse en condiciones específicas para formar derivados oxidados.
Reducción: Las reacciones de reducción pueden modificar los grupos funcionales en this compound, alterando potencialmente su actividad.
Reactivos y Condiciones Comunes:
Oxidación: Los agentes oxidantes comunes incluyen el peróxido de hidrógeno y el permanganato de potasio.
Reducción: Se utilizan agentes reductores como el borohidruro de sodio y el hidruro de aluminio y litio.
Sustitución: Se pueden utilizar varios nucleófilos y electrófilos en condiciones controladas para lograr reacciones de sustitución.
Productos Principales: Los productos principales formados a partir de estas reacciones incluyen derivados oxidados, reducidos y sustituidos de this compound, cada uno con posibles propiedades farmacológicas diferentes .
Comparación Con Compuestos Similares
Efavirenz: Another non-nucleoside inhibitor used in the treatment of HIV infection.
Tipranavir: A protease inhibitor used in combination with other antiretroviral agents for the treatment of HIV.
Comparison: Dasabuvir is unique in its specific targeting of the HCV NS5B polymerase, whereas Efavirenz and Tipranavir target different viral enzymes. This compound’s high specificity for the NS5B polymerase makes it particularly effective against HCV genotype 1, while Efavirenz and Tipranavir are used for HIV treatment .
Propiedades
IUPAC Name |
N-[6-[3-tert-butyl-5-(2,4-dioxopyrimidin-1-yl)-2-methoxyphenyl]naphthalen-2-yl]methanesulfonamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C26H27N3O5S/c1-26(2,3)22-15-20(29-11-10-23(30)27-25(29)31)14-21(24(22)34-4)18-7-6-17-13-19(28-35(5,32)33)9-8-16(17)12-18/h6-15,28H,1-5H3,(H,27,30,31) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
NBRBXGKOEOGLOI-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)(C)C1=CC(=CC(=C1OC)C2=CC3=C(C=C2)C=C(C=C3)NS(=O)(=O)C)N4C=CC(=O)NC4=O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C26H27N3O5S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID301025953 |
Source
|
| Record name | Dasabuvir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID301025953 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
493.6 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain of the NS5B polymerase, and is therefore referred to as a non-nucleoside NS5B-palm polymerase inhibitor. The EC50 values of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays were 7.7 nM and 1.8 nM, respectively. By binding to NS5b outside of the active site of the enzyme, dasabuvir induces a conformational change thereby preventing further elongation of the nascent viral genome. A limitation of binding outside of the active site is that these binding sites are poorly preserved across the viral genotypes. This results in a limited potential for cross-genotypic activity and increased potential for development of resistance. Dasabuvir is therefore limited to treating genotypes 1a and 1b, and must be used in combination with other antiviral products. |
Source
|
| Record name | Dasabuvir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09183 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
CAS No. |
1132935-63-7 |
Source
|
| Record name | Dasabuvir | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=1132935-63-7 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Dasabuvir [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=1132935637 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Dasabuvir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09183 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Dasabuvir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID301025953 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | DASABUVIR | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/DE54EQW8T1 | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
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Q1: What is the primary mechanism of action of Dasabuvir?
A1: this compound acts as a non-nucleoside inhibitor of the HCV NS5B polymerase, a key enzyme required for viral replication. [, , , ] It binds to the palm I site of the enzyme, inducing a conformational change that prevents RNA synthesis. []
Q2: How does this compound's binding to NS5B polymerase affect HCV replication?
A2: this compound's binding to the palm I site of the NS5B polymerase inhibits the enzyme's ability to synthesize RNA, effectively blocking viral replication. [, ]
Q3: Does this compound demonstrate activity against all HCV genotypes?
A3: No, this compound's activity is primarily restricted to HCV genotypes 1a and 1b. [, , ] It shows limited efficacy against other genotypes.
Q4: What is the molecular formula and weight of this compound?
A4: this compound has the molecular formula C28H29N3O5S and a molecular weight of 519.61 g/mol.
Q5: Is there spectroscopic data available for this compound?
A5: Yes, studies have used techniques like HPLC-DAD and LC-QToF-MS/MS to characterize this compound and its degradation products, providing spectroscopic data. []
Q6: How stable is this compound under various stress conditions?
A6: Studies have assessed this compound's stability under various stress conditions (acidic, alkaline, neutral, thermal, oxidative, and photolytic). [] It shows degradation primarily under alkaline conditions, leading to the formation of two degradation products. []
Q7: Have computational methods been used to study this compound?
A7: Yes, computational chemistry approaches, including molecular docking and molecular dynamics simulations, have been used to investigate this compound's interactions with the NS5B polymerase and to design potential derivatives. [, , ]
Q8: How do structural modifications of this compound affect its activity?
A8: Studies exploring this compound derivatives indicate that modifications to the methanesulfonamide moiety can influence its activity, safety, and toxicity profile. []
Q9: What challenges are associated with formulating this compound for oral delivery?
A9: this compound exhibits low aqueous solubility, posing challenges for oral bioavailability. [] It is a weak diacidic drug with a high propensity for solvate formation. []
Q10: How have these formulation challenges been addressed?
A10: The development of this compound as a monosodium monohydrate salt significantly enhanced its solubility, dissolution rate, and oral absorption, enabling its clinical development and commercialization. []
Q11: How is this compound metabolized in the body?
A11: this compound is primarily metabolized by CYP2C8 enzymes in the liver, with a minor contribution from CYP3A4. [, , ]
Q12: What are the major routes of this compound elimination?
A12: Following metabolism, this compound and its metabolites are primarily eliminated through feces, with minimal renal excretion. []
Q13: Are there any known drug-drug interactions involving this compound?
A13: Yes, this compound exhibits potential for drug-drug interactions, particularly with inhibitors of CYP2C8 like clopidogrel and gemfibrozil. [, , , ]
Q14: What is the efficacy of this compound in clinical trials for HCV?
A14: Clinical trials have demonstrated that this compound, in combination with other direct-acting antiviral agents, achieves high sustained virologic response (SVR) rates in patients with HCV genotype 1 infection, including those with compensated cirrhosis. [, , , ]
Q15: What are the known resistance mechanisms to this compound?
A15: Resistance to this compound can emerge through mutations in the NS5B gene, particularly at positions C316Y, M414T, Y448C, Y448H, and S556G. [, ]
Q16: Does this compound show cross-resistance with other HCV polymerase inhibitors?
A16: this compound demonstrates a distinct resistance profile compared to other polymerase inhibitors. [] It retains activity against replicons carrying mutations conferring resistance to nucleoside inhibitors or those in the thumb domain of NS5B. []
Q17: What are the common adverse effects associated with this compound?
A17: While generally well-tolerated, this compound has been associated with adverse events such as fatigue, headache, nausea, and diarrhea. [, , , ]
Q18: Are there strategies for targeted delivery of this compound?
A18: Currently, research focuses on optimizing oral delivery through formulation approaches rather than targeted delivery strategies.
Q19: Are there specific biomarkers used to predict this compound efficacy?
A19: While HCV RNA levels are used to monitor treatment response, specific biomarkers for predicting this compound efficacy are not yet established.
Q20: What analytical methods are used to quantify this compound?
A20: High-performance liquid chromatography (HPLC) coupled with ultraviolet (UV) or mass spectrometry (MS) detection is commonly employed to quantify this compound and its metabolites in biological samples. []
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