Ombitasvir
描述
奥比替沙韦是一种抗病毒药物，用于治疗丙型肝炎病毒 (HCV) 感染。 它是一种直接作用的抗病毒剂，可以抑制非结构蛋白 5A (NS5A)，该蛋白对于病毒复制和病毒体组装至关重要 。 奥比替沙韦通常与其他抗病毒剂（如帕瑞替普韦、利托那韦和达沙替尼）联合使用，以在慢性丙型肝炎患者中获得持续病毒学应答 (SVR) .
作用机制
奥比替沙韦通过抑制丙型肝炎病毒的非结构蛋白 5A (NS5A) 来发挥其抗病毒作用。 NS5A 对病毒复制和组装至关重要，其抑制会破坏病毒的生命周期，导致病毒载量减少 。 奥比替沙韦与 NS5A 结合，阻止其与其他病毒和宿主细胞成分相互作用，从而抑制病毒的复制 .
生化分析
Biochemical Properties
Ombitasvir is a potent inhibitor of NS5A, a protein essential for viral replication and virion assembly . It displays linear pharmacokinetics over the dose range evaluated . This compound is predominantly metabolized by amide hydrolysis followed by oxidative metabolism, and has low potential for drug interactions .
Cellular Effects
This compound, as part of combination therapy, is used to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV) . It acts by inhibiting the HCV protein NS5A, which is essential for viral replication and virion assembly .
Molecular Mechanism
The molecular mechanism of this compound involves the inhibition of the HCV protein NS5A . NS5A is a protein that is essential for viral replication and virion assembly. By inhibiting this protein, this compound prevents the virus from replicating and assembling new virions .
Temporal Effects in Laboratory Settings
In laboratory settings, this compound has shown to be effective in achieving a sustained virologic response (SVR) after 12 weeks of daily therapy . The treatment with this compound is associated with very minimal side effects, with the most common being headache and fatigue .
Metabolic Pathways
This compound is mainly metabolized by amide hydrolysis followed by CYP2C8-mediated oxidative metabolism . The drug is mainly excreted in the feces (90.2%) with very little excreted in the urine (1.91%) .
Transport and Distribution
This compound displays high plasma protein binding (~99.9%) and has an apparent volume of distribution of 173 liters . The drug is mainly excreted in the feces (90.2%) with very little excreted in the urine (1.91%) .
Subcellular Localization
Given its mechanism of action, it can be inferred that this compound likely interacts with the HCV NS5A protein within the host cell where the viral replication and assembly occur .
准备方法
合成路线和反应条件
奥比替沙韦的合成涉及多个步骤，包括关键中间体的形成及其随后的偶联反应条件通常涉及使用有机溶剂、催化剂和试剂，如乙腈、磷酸盐缓冲液和醋酸铵 .
工业生产方法
在工业生产中，奥比替沙韦是使用大规模化学工艺合成的，以确保高产率和纯度。该过程涉及优化反应条件、纯化步骤和质量控制措施，以满足监管标准。 高效液相色谱 (HPLC) 和液相色谱-串联质谱 (LC-MS/MS) 是常用的分析技术，用于监控合成并确保最终产品的质量 .
化学反应分析
反应类型
奥比替沙韦经历了几种类型的化学反应，包括：
常用试剂和条件
奥比替沙韦合成和反应中使用的常用试剂包括乙腈、磷酸盐缓冲液、醋酸铵和各种有机溶剂。 反应条件被仔细控制，以实现所需的化学转化并确保化合物的稳定性 .
主要形成的产物
科学研究应用
Treatment of Hepatitis C
Ombitasvir is primarily indicated for the treatment of chronic hepatitis C, especially in genotypes 1 and 4. It is used in combination regimens that may include:
- Paritaprevir : A protease inhibitor.
- Ritonavir : A booster that enhances the effectiveness of paritaprevir.
- Dasabuvir : An additional polymerase inhibitor.
- Ribavirin : An older antiviral that can be added to enhance response rates.
Efficacy Data
Clinical trials have demonstrated high sustained virologic response rates (SVR12) in patients treated with this compound-based regimens. Table 1 summarizes some key efficacy findings from various studies:
Safety Profile
The safety profile of this compound has been generally favorable. Most adverse events reported are mild to moderate, with serious adverse events being rare. Common side effects include fatigue, headache, and nausea. The overall safety outcomes are consistent with those observed in clinical trials.
Adverse Events Summary
| Adverse Event | Frequency (%) |
|---|---|
| Fatigue | 10 - 15 |
| Headache | 5 - 10 |
| Nausea | 5 - 10 |
| Serious AEs | <1 |
Real-World Evidence
Real-world studies have confirmed the efficacy of this compound-based treatments outside controlled clinical trial settings. For instance, a study involving over 800 patients showed an SVR12 rate of approximately 98%, indicating that outcomes in routine practice are comparable to those seen in clinical trials .
Case Studies
- Case Study: Treatment-Naïve Patients
- Case Study: Patients with Cirrhosis
相似化合物的比较
奥比替沙韦属于一类称为 NS5A 抑制剂的直接作用抗病毒剂。该类别中的类似化合物包括：
利巴韦林： 另一种 NS5A 抑制剂，与索非布韦联合使用，用于治疗丙型肝炎。
达拉替尼： 一种 NS5A 抑制剂，与其他抗病毒剂联合使用，用于治疗丙型肝炎。
埃尔巴斯韦： 一种 NS5A 抑制剂，与格拉索普韦联合使用，用于治疗丙型肝炎。
与这些类似化合物相比，奥比替沙韦与帕瑞替普韦、利托那韦和达沙替尼的联合使用是独一无二的，这提供了全面而高效的抗病毒方案，副作用最小 .
生物活性
Ombitasvir is a direct-acting antiviral (DAA) agent primarily used in the treatment of chronic Hepatitis C virus (HCV) infections. It functions by inhibiting the HCV non-structural protein 5A (NS5A), which plays a crucial role in viral replication and assembly. This article explores the biological activity of this compound, including its pharmacodynamics, clinical efficacy, safety profiles, and real-world applications.
This compound specifically targets the NS5A protein of HCV, which is essential for the virus's lifecycle. The inhibition of NS5A disrupts several processes:
- Viral Replication : this compound impedes the replication complex formation necessary for viral RNA synthesis.
- Virion Assembly : By affecting the assembly of new virions, it reduces the overall viral load in infected individuals.
Pharmacokinetics
The pharmacokinetic profile of this compound is characterized by:
- Absorption : Peak plasma concentrations are reached approximately 5 hours post-administration, with an absolute bioavailability of 48%. Fatty meals can significantly increase its exposure.
- Distribution : this compound has a large volume of distribution (173 liters) and is highly protein-bound (99.9%).
- Metabolism and Elimination : It undergoes amide hydrolysis followed by CYP2C8-mediated metabolism, with approximately 90% excreted via feces and a half-life ranging from 21 to 25 hours .
Efficacy in Clinical Trials
This compound is often used in combination with other DAAs such as paritaprevir and ritonavir. The effectiveness of these combinations has been demonstrated in multiple clinical trials:
In a notable study involving 209 patients, a sustained virologic response (SVR) was achieved in 99% of participants at 12 weeks post-treatment, indicating high efficacy even in previously treated patients .
Safety Profile
The safety profile of this compound is generally favorable. Commonly reported adverse effects include:
- Mild Symptoms : Headaches and fatigue are the most frequently observed side effects.
- Serious Adverse Events : Occurred in about 3.8% of patients, including hepatic decompensation and renal insufficiency .
In a comprehensive analysis involving over 3,800 patients, adverse events were predominantly mild and manageable, confirming its tolerability across diverse patient populations .
Case Studies
Several case studies reinforce the efficacy and safety of this compound in real-world settings:
- AMBER Study : This study evaluated the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with chronic hepatitis C. Results showed that all Child–Pugh B patients achieved SVR, highlighting its utility even in those with moderate liver disease .
- Spanish Cohort Study : A representative sample of patients demonstrated that this compound-based regimens were effective and well-tolerated among both monoinfected and HIV-coinfected individuals, with SVR rates consistent with clinical trial data .
属性
IUPAC Name |
methyl N-[(2S)-1-[(2S)-2-[[4-[(2S,5S)-1-(4-tert-butylphenyl)-5-[4-[[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]phenyl]pyrrolidin-2-yl]phenyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C50H67N7O8/c1-30(2)42(53-48(62)64-8)46(60)55-28-10-12-40(55)44(58)51-35-20-14-32(15-21-35)38-26-27-39(57(38)37-24-18-34(19-25-37)50(5,6)7)33-16-22-36(23-17-33)52-45(59)41-13-11-29-56(41)47(61)43(31(3)4)54-49(63)65-9/h14-25,30-31,38-43H,10-13,26-29H2,1-9H3,(H,51,58)(H,52,59)(H,53,62)(H,54,63)/t38-,39-,40-,41-,42-,43-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
PIDFDZJZLOTZTM-KHVQSSSXSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)C(C(=O)N1CCCC1C(=O)NC2=CC=C(C=C2)C3CCC(N3C4=CC=C(C=C4)C(C)(C)C)C5=CC=C(C=C5)NC(=O)C6CCCN6C(=O)C(C(C)C)NC(=O)OC)NC(=O)OC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)NC2=CC=C(C=C2)[C@@H]3CC[C@H](N3C4=CC=C(C=C4)C(C)(C)C)C5=CC=C(C=C5)NC(=O)[C@@H]6CCCN6C(=O)[C@H](C(C)C)NC(=O)OC)NC(=O)OC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C50H67N7O8 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID201027920 |
Source
|
| Record name | Ombitasvir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID201027920 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
894.1 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Ombitasvir is an inhibitor of the HCV non-structural protein 5A. While the precise role of this protein is unknown, it is essential to viral replication and virion assembly. Potential modes of action of NS5A inhibitors like Elbasvir include blocking signaling interactions, redistribution of NS5A from the endoplasmic reticulum to the surface of lipid droplets, and modification of the HCV replication complex. |
Source
|
| Record name | Ombitasvir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09296 | |
| 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. |
1258226-87-7 |
Source
|
| Record name | Ombitasvir | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=1258226-87-7 | |
| 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 | Ombitasvir [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=1258226877 | |
| 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 | Ombitasvir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09296 | |
| 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 | Ombitasvir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID201027920 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | OMBITASVIR | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/2302768XJ8 | |
| 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. | |
体外研究产品的免责声明和信息
请注意，BenchChem 上展示的所有文章和产品信息仅供信息参考。 BenchChem 上可购买的产品专为体外研究设计，这些研究在生物体外进行。体外研究，源自拉丁语 "in glass"，涉及在受控实验室环境中使用细胞或组织进行的实验。重要的是要注意，这些产品没有被归类为药物或药品，他们没有得到 FDA 的批准，用于预防、治疗或治愈任何医疗状况、疾病或疾病。我们必须强调，将这些产品以任何形式引入人类或动物的身体都是法律严格禁止的。遵守这些指南对确保研究和实验的法律和道德标准的符合性至关重要。
