Dasabuvir
Vue d'ensemble
Description
Dasabuvir, commercialisé sous le nom de marque Exviera, est un médicament antiviral utilisé pour le traitement de l'infection chronique par le virus de l'hépatite C (VHC). Il s'agit d'un inhibiteur non nucléosidique de la polymérase ARN dépendante de l'ARN du VHC, ciblant spécifiquement la polymérase NS5B . Le this compound est souvent utilisé en association avec d'autres agents antiviraux tels que l'ombitasvir, le paritaprevir et le ritonavir pour obtenir une réponse virologique durable (RVS) chez les patients .
Mécanisme D'action
Target of Action
Dasabuvir primarily targets the Hepatitis C Virus (HCV) NS5B RNA-dependent RNA polymerase . This enzyme is essential for the replication of the viral genome . The NS5B polymerase is a key component in the life cycle of the HCV, making it a prime target for antiviral agents like this compound .
Mode of Action
This compound is a non-nucleoside inhibitor that binds to the palm domain of the NS5B polymerase . This binding induces a conformational change in the polymerase, rendering it unable to elongate viral RNA . This effectively terminates RNA polymerization and stops the replication of the HCV’s genome .
Biochemical Pathways
The binding sites for non-nucleoside NS5B inhibitors like this compound are poorly conserved across HCV genotypes . This leads to the restriction of this compound’s use to genotype 1 only . The inhibition of the NS5B polymerase disrupts the viral replication process, preventing the virus from multiplying and infecting new cells .
Pharmacokinetics
This compound is primarily metabolized by cytochrome P450 (CYP) 2C8, with a minor contribution from CYP3A . Biotransformation of this compound forms the M1 metabolite, which retains antiviral activity . This compound exhibits linear pharmacokinetics with a terminal half-life of approximately 5–8 hours, allowing for twice-daily dosing . The M1 metabolite of this compound is the major metabolite in plasma and has a half-life similar to that of this compound .
Result of Action
The result of this compound’s action is a decrease in the amount of HCV in the body . By inhibiting the NS5B polymerase, this compound prevents the virus from replicating and spreading inside the body . This leads to a sustained virologic response (SVR), which is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality .
Action Environment
The action of this compound can be influenced by several environmental factors. For instance, the presence of strong CYP2C8 inhibitors can increase this compound exposures by more than tenfold, while coadministration with strong CYP3A inhibitors can increase this compound exposures by less than 50% . Furthermore, coadministration of this compound with a CYP3A inducer can decrease this compound exposures by 55–70% . Therefore, coadministration of this compound with strong CYP2C8 inhibitors or strong CYP3A/CYP2C8 inducers is contraindicated .
Analyse Biochimique
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 .
Méthodes De Préparation
Voies de synthèse et conditions réactionnelles : La synthèse du Dasabuvir implique plusieurs étapes, à partir de matières premières disponibles dans le commerce. Les étapes clés comprennent la formation de la portion méthanesulfonamide et le couplage des groupes naphtyle et pyrimidinyle. Les conditions réactionnelles impliquent généralement l'utilisation de solvants organiques, de catalyseurs et de températures contrôlées pour assurer un rendement élevé et une pureté élevée .
Méthodes de production industrielle : La production industrielle du this compound suit une voie de synthèse similaire, mais elle est optimisée pour une fabrication à grande échelle. Cela comprend l'utilisation de réacteurs à écoulement continu, de systèmes automatisés et de mesures rigoureuses de contrôle qualité pour assurer la cohérence et la conformité aux normes réglementaires .
Analyse Des Réactions Chimiques
Types de réactions : Le Dasabuvir subit diverses réactions chimiques, notamment :
Oxydation : Le this compound peut être oxydé dans des conditions spécifiques pour former des dérivés oxydés.
Réduction : Les réactions de réduction peuvent modifier les groupes fonctionnels du this compound, ce qui peut altérer son activité.
Réactifs et conditions courantes :
Oxydation : Les agents oxydants courants comprennent le peroxyde d'hydrogène et le permanganate de potassium.
Réduction : Des agents réducteurs tels que le borohydrure de sodium et l'hydrure de lithium et d'aluminium sont utilisés.
Substitution : Différents nucléophiles et électrophiles peuvent être utilisés dans des conditions contrôlées pour réaliser des réactions de substitution.
Produits principaux : Les principaux produits formés à partir de ces réactions comprennent des dérivés oxydés, réduits et substitués du this compound, chacun ayant des propriétés pharmacologiques potentiellement différentes .
4. Applications de la recherche scientifique
Le this compound a plusieurs applications de recherche scientifique, notamment :
Industrie : Employé dans le développement de thérapies antivirales et comme composé de référence dans les études pharmacologiques.
5. Mécanisme d'action
Le this compound exerce ses effets antiviraux en inhibant la polymérase ARN dépendante de l'ARN du VHC codée par le gène NS5B. Il se lie au domaine palmaire de la polymérase NS5B, induisant un changement conformationnel qui rend la polymérase incapable d'allonger l'ARN viral. Cette inhibition empêche la réplication du génome viral, conduisant à une réduction de la charge virale et atteignant finalement une réponse virologique durable .
Composés similaires :
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.
Comparaison : Le this compound est unique en son ciblage spécifique de la polymérase NS5B du VHC, tandis que l'Efavirenz et le Tipranavir ciblent différentes enzymes virales. La haute spécificité du this compound pour la polymérase NS5B le rend particulièrement efficace contre le génotype 1 du VHC, tandis que l'Efavirenz et le Tipranavir sont utilisés pour le traitement du VIH .
Applications De Recherche Scientifique
Dasabuvir has several scientific research applications, including:
Comparaison Avec Des Composés Similaires
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 .
Propriétés
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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