Oseltamivir
Übersicht
Beschreibung
Oseltamivir, marketed under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, the viruses that cause the flu . It is a neuraminidase inhibitor, which means it blocks the function of the viral neuraminidase protein, preventing the virus from spreading within the body .
Wirkmechanismus
Target of Action
Oseltamivir, marketed as Tamiflu, is an antiviral medication primarily targeting the influenza viruses A and B . The primary target of this compound is the viral neuraminidase enzyme found on the surface of the influenza virus . This enzyme plays a crucial role in the release of new virus particles from infected host cells .
Mode of Action
This compound exerts its antiviral activity by inhibiting the activity of the viral neuraminidase enzyme . This inhibition prevents the budding of the virus from the host cell, thereby suppressing viral replication and infectivity . It’s worth noting that this compound is a competitive inhibitor of influenza neuraminidase .
Biochemical Pathways
This compound is ingested in the form of a prodrug, this compound phosphate, which is rapidly converted by hepatic esterases into the active metabolite, this compound carboxylate . This active metabolite then inhibits influenza A and B neuraminidases . The inhibition of neuraminidase prevents the release of progeny virions from infected host cells, thereby reducing viral replication .
Pharmacokinetics
This compound has a high bioavailability and penetrates sites of infection at concentrations sufficient to inhibit viral replication . The pharmacokinetics of this compound and this compound carboxylate are dose-proportional after repeated doses of up to 500 mg twice daily . This predictable profile means that this compound is suitable for use in diverse patient populations, including young children, elderly patients, various ethnic groups, and those with renal or hepatic impairment .
Result of Action
The use of this compound can shorten the duration of fever and illness symptoms, and may reduce the risk of some complications, including pneumonia and respiratory failure . The clinical benefit of this compound is greatest when administered within 48 hours of the onset of influenza symptoms .
Action Environment
The effectiveness of this compound can be influenced by environmental factors. For instance, this compound-resistant strains of influenza have emerged, posing a challenge to the drug’s efficacy . Additionally, the continuous release and persistence of this compound in the environment, even at trace concentrations, has become an emerging environmental problem which may impose toxicity to the organisms present in the surroundings .
Wissenschaftliche Forschungsanwendungen
Oseltamivir has a wide range of scientific research applications:
Chemistry: Used as a model compound in the study of chiral synthesis and biocatalysis.
Biology: Studied for its interactions with viral proteins and its role in inhibiting viral replication.
Medicine: Widely used in the treatment and prevention of influenza.
Industry: Employed in the large-scale production of antiviral medications.
Biochemische Analyse
Biochemical Properties
Oseltamivir exerts its antiviral activity by inhibiting the activity of the viral neuraminidase enzyme found on the surface of the virus . This enzyme cleaves the sialic acid which is found on glycoproteins on the surface of human cells that helps new virions to exit the cell . By inhibiting this enzyme, this compound prevents budding from the host cell, viral replication, and infectivity .
Cellular Effects
This compound has been shown to have significant impact on virological parameters. It can shorten the duration of fever and illness symptoms, and may reduce the risk of some complications (including pneumonia and respiratory failure) . Its effectiveness decreases significantly after 48 hours of the onset of influenza symptoms .
Molecular Mechanism
This compound is a competitive inhibitor of influenza’s neuraminidase enzyme . It binds to the active site of the neuraminidase enzyme, preventing it from cleaving sialic acid residues on the surface of the host cell . This inhibits the release of new virus particles from the host cell, thereby limiting the spread of the virus .
Temporal Effects in Laboratory Settings
This compound has been shown to have a predictable linear pharmacokinetic profile . The clinical benefit of use of this compound is greatest when administered within 48 hours of the onset of influenza symptoms . Antiviral treatment might be beneficial when initiated after 48 hours for patients with severe, complicated or progressive illness or for hospitalized patients .
Dosage Effects in Animal Models
In animal models, this compound has been shown to have a significant impact on virological parameters. The in vivo efficacy of this compound is lower against viruses that show reduced inhibition by this compound in laboratory testing .
Metabolic Pathways
This compound is a prodrug that is rapidly metabolized by hepatic carboxylesterase 1 (CES1) into its active metabolite, this compound carboxylate (OC) . This reaction releases the active metabolite, which is a potent neuraminidase inhibitor that inhibits the influenza virus .
Transport and Distribution
This compound is systemically distributed to infection sites at concentrations sufficient to inhibit a range of influenza virus neuraminidases . The clearance of this compound carboxylate was found to be 15.8 l/hour, lower than the reported mean value of 21.5 l/hour in healthy adults .
Subcellular Localization
The major subcellular localizations of this compound are the cytosol and plasma membranes
Vorbereitungsmethoden
Synthetic Routes and Reaction Conditions
The synthesis of oseltamivir is complex due to its three contiguous chiral centers. One of the initial scalable routes to this compound started from shikimic acid, a natural product . The process involves multiple steps, including protection and deprotection of functional groups, formation of the cyclohexene ring, and introduction of the amino and acetamido groups .
Industrial Production Methods
Industrial production of this compound often involves biocatalytic methods due to their mild, highly selective, and environmentally benign nature . For example, the use of enzymes in the asymmetric synthesis of amino acid components and the fermentative production of structurally complex intermediates are common . Another method involves the use of organic solvents and catalysts like Lindlar catalyst under specific conditions to achieve high yields .
Analyse Chemischer Reaktionen
Types of Reactions
Oseltamivir undergoes various chemical reactions, including:
Oxidation: Conversion of the hydroxyl group to a carbonyl group.
Reduction: Reduction of the azido group to an amino group.
Substitution: Introduction of functional groups like acetamido and amino groups.
Common Reagents and Conditions
Common reagents used in these reactions include hydrogen gas, Lindlar catalyst, and organic solvents like methanol and acetone . Reaction conditions often involve specific temperatures and pressures to ensure high yields and purity .
Major Products
The major products formed from these reactions include this compound carboxylate, which is the active metabolite of this compound .
Vergleich Mit ähnlichen Verbindungen
Similar Compounds
Zanamivir: Another neuraminidase inhibitor used to treat influenza.
Laninamivir: A long-acting neuraminidase inhibitor.
Peramivir: An intravenous neuraminidase inhibitor.
Uniqueness
Oseltamivir is unique due to its oral bioavailability and its ability to be used both for treatment and prevention of influenza . Unlike zanamivir, which is inhaled, this compound can be taken orally, making it more convenient for patients . Additionally, its prodrug nature allows for efficient conversion to its active form in the body .
Eigenschaften
IUPAC Name |
ethyl (3R,4R,5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexene-1-carboxylate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C16H28N2O4/c1-5-12(6-2)22-14-9-11(16(20)21-7-3)8-13(17)15(14)18-10(4)19/h9,12-15H,5-8,17H2,1-4H3,(H,18,19)/t13-,14+,15+/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
VSZGPKBBMSAYNT-RRFJBIMHSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCC(CC)OC1C=C(CC(C1NC(=O)C)N)C(=O)OCC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CCC(CC)O[C@@H]1C=C(C[C@@H]([C@H]1NC(=O)C)N)C(=O)OCC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C16H28N2O4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID9044291 |
Source
|
| Record name | Oseltamivir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9044291 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
312.40 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Oseltamivir | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014343 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
Soluble, 6.86e-01 g/L |
Source
|
| Record name | Oseltamivir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00198 | |
| 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 | Oseltamivir | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014343 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate) which is a potent and selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important for viral entry into uninfected cells, for the release of recently formed virus particles from infected cells, and for the further spread of the infectious virus in the body. Oseltamivir activity reduces viral shedding and infectivity. Oseltamivir is effective agaisnt viral neuraminidases of influenza A (including pandemic H1N1) and influenza B., Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. |
Source
|
| Record name | Oseltamivir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00198 | |
| 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 | OSELTAMIVIR | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7433 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
196618-13-0, 204255-11-8 |
Source
|
| Record name | Oseltamivir | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=196618-13-0 | |
| 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 | Oseltamivir [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0196618130 | |
| 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 | Oseltamivir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00198 | |
| 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 | Oseltamivir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9044291 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | OSELTAMIVIR | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/20O93L6F9H | |
| 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. | |
| Record name | OSELTAMIVIR | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7433 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Oseltamivir | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014343 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
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: How does oseltamivir interact with its target and what are the downstream effects?
A1: this compound phosphate itself is a prodrug, meaning it is inactive until metabolized in the body. [, , ] It is converted by hepatic esterases into its active metabolite, this compound carboxylate. [] this compound carboxylate functions by selectively inhibiting neuraminidase, an enzyme crucial for the replication and release of influenza A and B viruses. [, , , ] By blocking neuraminidase, this compound prevents the release of newly formed viral particles from infected cells, thereby inhibiting the spread of the virus within the host. []
Q2: What is the molecular formula, weight, and available spectroscopic data for this compound?
A2: Unfortunately, the provided research papers do not delve into the specific spectroscopic characterization of this compound. While the molecular formula (C16H28N2O4) and weight (312.4 g/mol) are widely available in drug databases, the papers focus primarily on clinical and biological aspects rather than detailed spectroscopic analysis.
Q3: The provided research does not seem to cover aspects like material compatibility, catalytic properties, or computational studies of this compound. Why is that?
A3: You are right to point that out. The research focuses primarily on this compound's application as an antiviral drug. Therefore, aspects like material compatibility and stability, which are more relevant to material science, are not discussed. Similarly, this compound does not function as a catalyst, hence the lack of studies on catalytic properties. While computational chemistry could offer insights into this compound's interactions, the available research emphasizes experimental studies on its biological activity and pharmacokinetics.
Q4: How do structural modifications of this compound impact its activity, potency, and selectivity?
A4: Although the provided research doesn't focus on synthesizing this compound analogs, it highlights a crucial structure-activity relationship. The conversion of this compound phosphate to its active form, this compound carboxylate, is essential for its antiviral activity. [, , ] Studies demonstrate that mutations affecting the carboxylesterase 1 enzyme, responsible for this conversion, can significantly impair this compound's efficacy. [] This underscores the importance of the carboxylate moiety for the drug's interaction with neuraminidase and its subsequent antiviral effect.
Q5: Can you elaborate on the pharmacokinetics of this compound, including its absorption, distribution, metabolism, and excretion (ADME)?
A7: this compound is administered orally as a prodrug and is rapidly absorbed. [] It undergoes rapid conversion to its active metabolite, this compound carboxylate, primarily by hepatic esterases. [, ] this compound carboxylate demonstrates high bioavailability and is widely distributed in the body, reaching therapeutic concentrations in various sites, including the lungs. [, ] It is primarily eliminated renally, with dose adjustments recommended for patients with renal impairment. [, ]
Q6: What is the impact of co-administration of other drugs, such as probenecid, on this compound's pharmacokinetics?
A9: Research shows that co-administration with probenecid, a drug that inhibits renal tubular secretion, can increase plasma concentrations of this compound carboxylate. [] While this interaction may allow for reduced this compound doses, it could also increase the risk of drug interactions and potentially impact tolerability. []
Q7: What in vitro and in vivo models have been used to evaluate the efficacy of this compound against influenza viruses?
A10: Several studies utilized both in vitro and in vivo models to evaluate this compound's efficacy. In vitro studies often employed Madin-Darby canine kidney cells infected with various influenza A strains, including H1N1, H3N2, and H5N1 subtypes. [, , ] These studies measured parameters like viral titer reduction, inhibition of viral neuraminidase activity, and the emergence of drug resistance mutations. [, , ] In vivo studies predominantly used mouse models infected with different influenza A strains to assess this compound's therapeutic and prophylactic efficacy. [, , ] These studies typically monitored survival rates, body weight changes, lung viral titers, and the extent of lung damage as indicators of treatment effectiveness. [, , ]
Q8: Have there been any clinical trials evaluating the effectiveness of this compound in treating influenza in humans?
A11: Yes, numerous clinical trials have assessed this compound's effectiveness in treating influenza in humans. Many studies focused on its use in various populations, including adults, children, and specific high-risk groups like hospitalized patients. [, , , , , , , , , ] These trials assessed outcomes like time to alleviation of symptoms, reduction in viral shedding, incidence of influenza-related complications (e.g., pneumonia, otitis media), hospitalization rates, and mortality. [, , , , , , , , , ] The research emphasizes that early initiation of this compound treatment is crucial for maximizing its therapeutic benefits. []
Q9: What are the known mechanisms of resistance to this compound, and is there any evidence of cross-resistance with other antiviral drugs?
A12: A significant concern is the emergence of this compound resistance, primarily attributed to mutations in the viral neuraminidase gene. [, , , , ] The most prevalent mutation is H275Y, initially observed in seasonal H1N1 viruses and later identified in pandemic H1N1 2009 strains. [, , , ] This mutation alters the binding site of neuraminidase, reducing this compound's ability to inhibit the enzyme effectively. [] Research indicates that this compound-resistant strains can emerge both in vitro and in vivo, highlighting the potential for resistance development during treatment. [, ] Studies investigating other antiviral drugs, like amantadine and ribavirin, demonstrate that combinations of these drugs with this compound can exhibit synergistic effects against certain influenza strains. [, ] This suggests that combination therapy might be a viable strategy for combating the emergence of drug resistance. [, ]
Q10: Due to the focus on scientific aspects, the provided research excludes detailed information on toxicology, drug delivery strategies, and biomarkers related to this compound. Why is this information absent?
A10: The research primarily aims to provide insights into the scientific basis of this compound's action, focusing on its mechanism, efficacy, and resistance development. While understanding its toxicology, drug delivery, and biomarkers is crucial for clinical practice, these topics are beyond the scope of these specific research papers.
Q11: What analytical techniques are commonly employed to characterize and quantify this compound?
A14: Several analytical methods were employed throughout the research. High-performance liquid chromatography (HPLC) coupled with various detection methods, such as UV detection, was widely used to quantify this compound and its metabolite in biological samples. [] Genotyping assays, particularly real-time polymerase chain reaction (PCR) techniques, were utilized to identify specific mutations in the influenza virus genome associated with this compound resistance. [, , ] These techniques enabled researchers to track the emergence and spread of drug-resistant strains. [, , ]
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