达沙布韦
概述
描述
达沙布韦，商品名为 Exviera，是一种抗病毒药物，用于治疗慢性丙型肝炎病毒 (HCV) 感染。 它是一种非核苷类抑制剂，靶向 HCV RNA 依赖性 RNA 聚合酶，特别是针对 NS5B 聚合酶 。 达沙布韦通常与其他抗病毒药物（如奥比替韦、帕利替韦和利托那韦）联合使用，以在患者中实现持续病毒学应答 (SVR) .
科学研究应用
达沙布韦在科学研究中有多种应用，包括：
作用机制
达沙布韦通过抑制由 NS5B 基因编码的 HCV RNA 依赖性 RNA 聚合酶来发挥其抗病毒作用。它与 NS5B 聚合酶的掌叶域结合，诱导构象改变，使聚合酶无法延伸病毒 RNA。 这种抑制阻止了病毒基因组的复制，导致病毒载量减少，最终实现持续病毒学应答 .
类似化合物：
依法韦仑： 另一种用于治疗 HIV 感染的非核苷类抑制剂.
比较： 达沙布韦在靶向 HCV NS5B 聚合酶方面是独一无二的，而依法韦仑和替拉那韦靶向不同的病毒酶。 达沙布韦对 NS5B 聚合酶的高度特异性使其对 HCV 1 型特别有效，而依法韦仑和替拉那韦用于治疗 HIV .
生化分析
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. Dasabuvir 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 dasabuvir does not significantly affect human RNA polymerases, making it a potent antiviral agent with minimal off-target effects .
Cellular Effects
Dasabuvir has significant effects on infected hepatocytes, the primary target cells of HCV . By inhibiting the NS5B RNA polymerase, dasabuvir 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, dasabuvir 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 dasabuvir involves its binding to the NS5B RNA polymerase of HCV . Dasabuvir 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 dasabuvir 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, dasabuvir has been shown to be stable and effective over extended periods . Studies have demonstrated that dasabuvir maintains its antiviral activity for several days in cell culture systems . Prolonged exposure to dasabuvir can lead to the emergence of resistant viral strains, highlighting the importance of combination therapy to prevent resistance . The stability of dasabuvir in various formulations also ensures its efficacy in clinical use .
Dosage Effects in Animal Models
In animal models, the effects of dasabuvir vary with different dosages . At therapeutic doses, dasabuvir effectively reduces viral load without causing significant toxicity . At higher doses, dasabuvir 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
Dasabuvir is metabolized primarily in the liver by the cytochrome P450 enzyme system, particularly CYP3A4 . This enzyme converts dasabuvir into its inactive metabolites, which are then excreted via the bile and urine . The involvement of CYP3A4 in dasabuvir 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, dasabuvir is transported and distributed primarily in the cytoplasm, where it exerts its antiviral effects . Dasabuvir 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, dasabuvir accumulates in the cytoplasm and binds to the NS5B RNA polymerase .
Subcellular Localization
Dasabuvir 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 . Dasabuvir does not undergo significant post-translational modifications or targeting to other cellular compartments, ensuring its specific action against the viral polymerase .
准备方法
合成路线和反应条件： 达沙布韦的合成涉及多个步骤，从市售的起始原料开始。关键步骤包括甲磺酰胺部分的形成以及萘基和嘧啶基的偶联。 反应条件通常涉及使用有机溶剂、催化剂和控制温度，以确保高产率和纯度 .
工业生产方法： 达沙布韦的工业生产遵循类似的合成路线，但针对大规模生产进行了优化。 这包括使用连续流动反应器、自动化系统和严格的质量控制措施，以确保一致性和符合监管标准 .
化学反应分析
反应类型： 达沙布韦会发生各种化学反应，包括：
氧化： 达沙布韦在特定条件下可以被氧化形成氧化衍生物。
还原： 还原反应可以改变达沙布韦中的官能团，可能改变其活性。
常用试剂和条件：
氧化： 常用的氧化剂包括过氧化氢和高锰酸钾。
还原： 使用硼氢化钠和氢化铝锂等还原剂。
相似化合物的比较
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. Dasabuvir’s high specificity for the NS5B polymerase makes it particularly effective against HCV genotype 1, while Efavirenz and Tipranavir are used for HIV treatment .
属性
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: Dasabuvir 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 Dasabuvir's binding to NS5B polymerase affect HCV replication?
A2: Dasabuvir'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 Dasabuvir demonstrate activity against all HCV genotypes?
A3: No, Dasabuvir'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 Dasabuvir?
A4: Dasabuvir has the molecular formula C28H29N3O5S and a molecular weight of 519.61 g/mol.
Q5: Is there spectroscopic data available for Dasabuvir?
A5: Yes, studies have used techniques like HPLC-DAD and LC-QToF-MS/MS to characterize Dasabuvir and its degradation products, providing spectroscopic data. []
Q6: How stable is Dasabuvir under various stress conditions?
A6: Studies have assessed Dasabuvir'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 Dasabuvir?
A7: Yes, computational chemistry approaches, including molecular docking and molecular dynamics simulations, have been used to investigate Dasabuvir's interactions with the NS5B polymerase and to design potential derivatives. [, , ]
Q8: How do structural modifications of Dasabuvir affect its activity?
A8: Studies exploring Dasabuvir derivatives indicate that modifications to the methanesulfonamide moiety can influence its activity, safety, and toxicity profile. []
Q9: What challenges are associated with formulating Dasabuvir for oral delivery?
A9: Dasabuvir 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 Dasabuvir as a monosodium monohydrate salt significantly enhanced its solubility, dissolution rate, and oral absorption, enabling its clinical development and commercialization. []
Q11: How is Dasabuvir metabolized in the body?
A11: Dasabuvir is primarily metabolized by CYP2C8 enzymes in the liver, with a minor contribution from CYP3A4. [, , ]
Q12: What are the major routes of Dasabuvir elimination?
A12: Following metabolism, Dasabuvir and its metabolites are primarily eliminated through feces, with minimal renal excretion. []
Q13: Are there any known drug-drug interactions involving Dasabuvir?
A13: Yes, Dasabuvir exhibits potential for drug-drug interactions, particularly with inhibitors of CYP2C8 like clopidogrel and gemfibrozil. [, , , ]
Q14: What is the efficacy of Dasabuvir in clinical trials for HCV?
A14: Clinical trials have demonstrated that Dasabuvir, 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 Dasabuvir?
A15: Resistance to Dasabuvir can emerge through mutations in the NS5B gene, particularly at positions C316Y, M414T, Y448C, Y448H, and S556G. [, ]
Q16: Does Dasabuvir show cross-resistance with other HCV polymerase inhibitors?
A16: Dasabuvir 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 Dasabuvir?
A17: While generally well-tolerated, Dasabuvir has been associated with adverse events such as fatigue, headache, nausea, and diarrhea. [, , , ]
Q18: Are there strategies for targeted delivery of Dasabuvir?
A18: Currently, research focuses on optimizing oral delivery through formulation approaches rather than targeted delivery strategies.
Q19: Are there specific biomarkers used to predict Dasabuvir efficacy?
A19: While HCV RNA levels are used to monitor treatment response, specific biomarkers for predicting Dasabuvir efficacy are not yet established.
Q20: What analytical methods are used to quantify Dasabuvir?
A20: High-performance liquid chromatography (HPLC) coupled with ultraviolet (UV) or mass spectrometry (MS) detection is commonly employed to quantify Dasabuvir and its metabolites in biological samples. []
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