法匹拉韦
描述
法匹拉韦，也称为6-氟-3-羟基吡嗪-2-甲酰胺，是一种抗病毒药物，主要用于治疗日本的流感。它是由富山化学工业株式会社开发的。并且在治疗各种RNA病毒感染方面显示出潜力，包括埃博拉病毒、拉沙热和最近的COVID-19 . 法匹拉韦是一种吡嗪甲酰胺衍生物，通过抑制病毒RNA依赖性RNA聚合酶发挥作用，从而阻止病毒复制 .
科学研究应用
法匹拉韦因其抗病毒特性而被广泛研究。 它对多种RNA病毒显示出疗效，包括流感、埃博拉病毒和SARS-CoV-2 . 除了用于治疗病毒感染外，法匹拉韦还在研究其治疗其他疾病的潜力，如拉沙热和寨卡病毒 . 它具有广谱抗病毒活性，使其成为临床和研究环境中的宝贵工具。
作用机制
法匹拉韦是一种前药，在体内代谢成其活性形式，法匹拉韦-呋喃核糖-5’-三磷酸（法匹拉韦-RTP）。 这种活性形式抑制病毒RNA依赖性RNA聚合酶（RdRp），这种酶对病毒复制至关重要 . 法匹拉韦-RTP通过模拟鸟苷和腺苷，掺入病毒RNA中，导致RNA合成提前终止 .
生化分析
Biochemical Properties
Favipiravir functions as a prodrug and undergoes ribosylation and phosphorylation intracellularly to become the active form, favipiravir-ribofuranosyl-5’-triphosphate (favipiravir-RTP) . Favipiravir-RTP binds to and inhibits RNA dependent RNA polymerase (RdRp), which ultimately prevents viral transcription and replication . It mimics both guanosine and adenosine for the viral RdRP .
Cellular Effects
Favipiravir has shown to have significant effects on viral clearance and clinical improvement in patients with COVID-19 . It induces viral clearance by 7 days and contributes to clinical improvement within 14 days . Favipiravir significantly improved the clinical symptoms of infected patients, reduced viral titer and RNA copies in serum, and extended overall survival .
Molecular Mechanism
Favipiravir functions as a prodrug and undergoes ribosylation and phosphorylation intracellularly to become the active favipiravir-RTP . Favipiravir-RTP binds to and inhibits RNA dependent RNA polymerase (RdRp), which ultimately prevents viral transcription and replication . Favipiravir-RTP is a nucleoside analogue. It mimics both guanosine and adenosine for the viral RdRP .
Temporal Effects in Laboratory Settings
In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance . Favipiravir induces viral clearance by 7 days and contributes to clinical improvement within 14 days . The results indicated that favipiravir has strong possibility for treating COVID-19, especially in patients with mild-to-moderate illness .
Dosage Effects in Animal Models
In animal models, favipiravir significantly reduced virus titers 10- to 100-fold in sera at all three time points compared to vehicle-treated mice . And favipiravir treatment effectively reduced the virus copies by approximately 10-fold across the three time points, relative to vehicle-treated mice .
Metabolic Pathways
Favipiravir is extensively metabolized with metabolites excreted mainly in the urine . The antiviral undergoes hydroxylation primarily by aldehyde oxidase and to a lesser extent by xanthine oxidase to the inactive metabolite, T705M1 .
Transport and Distribution
The apparent volume of distribution of favipiravir is 15 - 20 L . Favipiravir is 54% plasma protein-bound . Of this fraction, 65% is bound to serum albumin and 6.5% is bound to ɑ1-acid glycoprotein .
Subcellular Localization
Given its mechanism of action, it can be inferred that favipiravir, after being converted to its active form favipiravir-RTP in the cytoplasm, likely localizes to the site of viral replication within the host cell, where it inhibits the viral RNA-dependent RNA polymerase .
准备方法
法匹拉韦可以通过多种途径合成。一种常见的方法从2-氨基吡嗪开始，其进行区域选择性氯化、溴化和钯催化氰化反应形成3,6-二氯吡嗪-2-腈。 该中间体随后进行亲核氟化、腈水合和羟基取代反应，得到法匹拉韦 . 另一种可扩展的合成方法使用丙二酸二乙酯作为起始原料，其在连续流动反应器中进行氢化和溴化反应，总收率为16% .
化学反应分析
相似化合物的比较
法匹拉韦与其他抗病毒化合物如瑞德西韦和利巴韦林相似，它们也靶向病毒RNA聚合酶。 法匹拉韦独特的吡嗪甲酰胺结构及其抑制多种RNA病毒的能力使其脱颖而出 . 其他类似的化合物包括T-1105和T-1106，它们在结构上相似，但在抗病毒活性谱方面有所不同 .
法匹拉韦的广谱抗病毒活性、独特的作用机制以及治疗各种病毒感染的潜力使其成为抗病毒研究和治疗中的重要化合物。
属性
IUPAC Name |
5-fluoro-2-oxo-1H-pyrazine-3-carboxamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C5H4FN3O2/c6-2-1-8-5(11)3(9-2)4(7)10/h1H,(H2,7,10)(H,8,11) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
ZCGNOVWYSGBHAU-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1=C(N=C(C(=O)N1)C(=O)N)F |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C5H4FN3O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID60948878 |
Source
|
| Record name | 6-Fluoro-3-hydroxypyrazine-2-carboxamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID60948878 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
157.10 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Solubility |
slightly soluble in water |
Source
|
| Record name | Favipiravir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB12466 | |
| 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) | |
Mechanism of Action |
The mechanism of action of favipiravir is novel compared to existing influenza antivirals that primarily prevent entry and exit of the virus from cells. The active favipiravir-RTP selectively inhibits RNA polymerase and prevents replication of the viral genome. There are several hypotheses as to how favipiravir-RTP interacts with RNA dependent RNA polymerase (RdRp). Some studies have shown that when favipiravir-RTP is incorporated into a nascent RNA strand, it prevents RNA strand elongation and viral proliferation. Studies have also found that the presence of purine analogs can reduce favipiravir’s antiviral activity, suggesting competition between favipiravir-RTP and purine nucleosides for RdRp binding. Although favipiravir was originally developed to treat influenza, the RdRp catalytic domain (favipiravir's primary target), is expected to be similar for other RNA viruses. This conserved RdRp catalytic domain contributes to favipiravir's broad-spectrum coverage. |
Source
|
| Record name | Favipiravir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB12466 | |
| 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. |
259793-96-9 |
Source
|
| Record name | Favipiravir | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=259793-96-9 | |
| 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 | Favipiravir [USAN:INN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0259793969 | |
| 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 | Favipiravir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB12466 | |
| 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 | 6-Fluoro-3-hydroxypyrazine-2-carboxamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID60948878 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | FAVIPIRAVIR | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/EW5GL2X7E0 | |
| 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. | |
Melting Point |
187℃ to 193℃ |
Source
|
| Record name | Favipiravir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB12466 | |
| 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) | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Q1: What is the primary mechanism of action of Favipiravir?
A1: Favipiravir is a broad-spectrum antiviral drug that acts as a selective inhibitor of RNA-dependent RNA polymerase (RdRp), an enzyme crucial for viral RNA replication and transcription. []
Q2: How does Favipiravir interact with RdRp?
A2: Favipiravir is a prodrug that is metabolized intracellularly into its active form, Favipiravir ribofuranosyl-5’-triphosphate (FAVI-RTP). FAVI-RTP acts as a purine analogue and competes with both guanine and adenine for binding to RdRp. This competition leads to the inhibition of viral RNA synthesis. [, , , ]
Q3: Does Favipiravir induce lethal mutagenesis in viruses?
A3: While initially thought to be a chain terminator, recent studies suggest Favipiravir can induce lethal mutagenesis in some viruses, like influenza A H1N1, by increasing the mutation rate in viral RNA beyond a sustainable threshold. []
Q4: What are the downstream effects of Favipiravir inhibiting RdRp?
A4: Inhibition of RdRp by Favipiravir leads to a decrease in viral RNA synthesis, ultimately hindering the replication and transcription processes essential for viral propagation. This results in a reduction of viral load and potentially limits the severity of viral infection. [, , ]
Q5: What is the molecular formula and weight of Favipiravir?
A6: The molecular formula of Favipiravir is C5H4FN3O2, and its molecular weight is 157.1 g/mol. []
Q6: What are the pharmacokinetic properties of Favipiravir?
A8: Favipiravir is a prodrug that is rapidly absorbed after oral administration and is metabolized primarily by aldehyde oxidase (AO) to its active form, FAVI-RTP. [] It exhibits a relatively short half-life in plasma, but its active metabolite, FAVI-RTP, has a longer intracellular half-life. [] This discrepancy suggests that while Favipiravir is cleared rapidly from the plasma, it might maintain sufficient intracellular concentrations of FAVI-RTP for a longer duration. []
Q7: Does the presence of other drugs influence the pharmacokinetics of Favipiravir?
A9: Yes, co-administration of Favipiravir with drugs metabolized by or affecting AO or xanthine oxidase (XO) can alter its pharmacokinetic profile. For instance, co-administration with pioglitazone, an AO substrate, altered Favipiravir's pharmacokinetics. Similarly, interactions were observed with citalopram (an AO substrate and modulator) and allopurinol (an AO substrate and XO inhibitor). [, ]
Q8: What is the relationship between Favipiravir plasma concentrations and its antiviral effect?
A10: In a study on uncomplicated influenza, achieving an average minimum plasma concentration (Cmin) of Favipiravir greater than 20 μg/mL was associated with enhanced antiviral activity, faster viral clearance, and quicker alleviation of symptoms compared to lower concentrations or placebo. []
Q9: Has resistance to Favipiravir been observed in viruses?
A13: Yes, although Favipiravir was initially thought to have a high barrier to resistance, studies have shown that resistance can develop, albeit at a lower rate compared to other antiviral drugs. [, ]
Q10: Which mutations are associated with Favipiravir resistance?
A14: In influenza A virus, a key mutation associated with Favipiravir resistance is K229R in the PB1 subunit of RdRp. [] This mutation confers resistance in vitro and in cell culture but comes at a cost to viral fitness. A compensatory mutation, P653L in the PA subunit, can restore viral fitness. [] Interestingly, the location of the K229R mutation within a conserved motif of RdRp raises the possibility that other RNA viruses might develop resistance through similar mutations. []
Q11: What are the known adverse effects associated with Favipiravir?
A16: Favipiravir has been associated with various adverse effects, including gastrointestinal disturbances, elevated liver enzymes, hyperuricemia, and potential teratogenicity. [, , , , , ] The incidence and severity of these effects can vary based on factors such as dosage, duration of treatment, and individual patient characteristics.
Q12: What toxicological effects has Favipiravir demonstrated in preclinical studies?
A17: Preclinical studies in rats have shown that Favipiravir administration, particularly at high doses, can induce oxidative stress, inflammation, and histopathological changes in the liver, kidneys, and lungs. [, , ] These findings underscore the importance of careful monitoring for potential toxicity in clinical settings.
Q13: What alternative routes of administration are being explored for Favipiravir?
A18: To potentially improve drug delivery directly to the lungs, researchers are developing an inhalation solution of Favipiravir. [] This approach aims to enhance drug concentration at the site of infection in respiratory illnesses like COVID-19.
Q14: What analytical methods are commonly used to quantify Favipiravir?
A19: High-performance liquid chromatography (HPLC) coupled with UV or tandem mass spectrometry (HPLC-MS/MS) are frequently used for the accurate and sensitive quantification of Favipiravir in biological matrices. [, , ]
Q15: Have any analytical methods been developed for monitoring Favipiravir treatment?
A20: While specific biomarkers for monitoring Favipiravir treatment are still under investigation, next-generation sequencing (NGS) has been proposed as a tool to track the drug's mutagenic effect on viruses. [] By analyzing the pattern of mutations induced by Favipiravir, researchers can potentially assess its antiviral activity and monitor for the emergence of resistance. []
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