拉替拉韦钾
概述
描述
拉替拉韦钾: 是一种主要用于治疗 HIV-1 感染的抗逆转录病毒药物。它是拉替拉韦的钾盐形式，拉替拉韦是一种 HIV 整合酶链转移抑制剂。该化合物是其类别中第一个于 2007 年获得美国 食品药品监督管理局 (FDA) 批准的药物 。 拉替拉韦钾通过抑制整合酶发挥作用，整合酶是病毒复制过程必不可少的酶 .
科学研究应用
Treatment of HIV Infection
Raltegravir potassium is indicated for the treatment of HIV-1 infection in both adults and pediatric patients. Its use is essential in achieving viral suppression when combined with other antiretroviral agents. The drug's mechanism involves inhibiting the integrase enzyme, which is crucial for viral replication.
Efficacy in Clinical Trials
Significant clinical trials have demonstrated the efficacy of raltegravir. For instance, in the BENCHMRK studies, patients treated with raltegravir showed a higher percentage of achieving viral loads below 50 copies/mL compared to those receiving placebo. Specifically, at week 156, 51% of patients on raltegravir achieved this milestone versus only 22% in the placebo group . Furthermore, after 240 weeks, the mean increase in CD4 cell counts was notable, indicating robust immune recovery among those treated with raltegravir .
Pharmacokinetics and Dosage
Raltegravir potassium is administered orally, typically at a dosage of 400 mg twice daily. It exhibits a favorable pharmacokinetic profile, with peak plasma concentrations reached approximately three hours post-dose. The drug shows dose-proportional absorption and does not significantly prolong the QTc interval, making it a safe option for many patients .
Table: Pharmacokinetic Parameters of Raltegravir
| Parameter | Value |
|---|---|
| Tmax | ~3 hours |
| AUC (Area Under Curve) | Dose-proportional |
| Cmax | Increases with dose |
Safety Profile and Side Effects
The safety profile of raltegravir potassium has been evaluated extensively. Common side effects include gastrointestinal disturbances and rash; however, severe adverse events are rare. Monitoring for hypersensitivity reactions and liver function is recommended during treatment .
Combination Therapy
Raltegravir is often used in combination with other antiretroviral drugs to enhance treatment efficacy and reduce the risk of resistance development. This combination approach is crucial for achieving sustained virologic suppression.
Case Study: Efficacy in Treatment-Naïve Patients
In a cohort study involving treatment-naïve patients, those receiving a regimen including raltegravir showed significantly improved outcomes compared to traditional therapies. The study reported that after 48 weeks, over 80% of participants achieved undetectable viral loads .
Potential Beyond HIV Treatment
Recent research suggests that raltegravir may have applications beyond HIV treatment. Investigations into its effects on other viral infections and its potential role in cancer therapy are ongoing. For example, studies are exploring how integrase inhibitors like raltegravir may influence cellular mechanisms relevant to oncogenesis .
作用机制
拉替拉韦钾抑制 HIV 整合酶，阻止病毒 DNA 整合到宿主细胞基因组中。这种抑制阻止了病毒的复制，从而降低了患者体内的病毒载量。 该化合物主要通过葡萄糖醛酸化代谢 .
准备方法
合成路线和反应条件: 拉替拉韦钾的合成涉及多个步骤，包括嘧啶酮中间体的选择性 N-甲基化。 该过程通常包括以下步骤 :
N-烷基化: 嘧啶酮中间体使用 (氯甲基)二甲基氯硅烷和氟化钾进行烷基化。
酰胺化: 烷基化产物与胺进行酰胺化。
去硅烷化: 最后一步涉及使用甲醇中的氟化钾进行去硅烷化。
工业生产方法: 拉替拉韦钾的工业生产涉及干法制粒技术来制备压片。 该过程包括将拉替拉韦与赋形剂混合，将混合物压缩成块，将块尺寸调整为颗粒，最后将颗粒压缩成片剂 .
化学反应分析
反应类型: 拉替拉韦钾会发生几种类型的化学反应，包括：
氧化: 它可以在特定条件下被氧化。
还原: 它可以使用适当的还原剂进行还原。
取代: 可以发生各种取代反应，尤其是涉及氟苯基的反应。
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: 可以使用硼氢化钠等还原剂。
主要产物: 从这些反应中形成的主要产物取决于所使用的具体试剂和条件。 例如，氧化可能生成羟基化衍生物，而还原可以生成脱氧化合物 .
相似化合物的比较
拉替拉韦钾与其他 HIV 整合酶抑制剂进行比较，例如：
- 艾维拉韦
- 多替拉韦
- 比克替拉韦
独特性: 拉替拉韦钾是第一个获批临床使用的整合酶抑制剂，为该类别中后续药物开创了先例。 它以快速作用和有效降低病毒载量而闻名 .
类似化合物：
- 艾维拉韦 : 另一种具有相似机制但药代动力学特性不同的整合酶抑制剂。
- 多替拉韦 : 以其比拉替拉韦更高的耐药性屏障而闻名。
- 比克替拉韦 : 提供一日一次给药，常用于联合疗法 .
生物活性
Raltegravir potassium is an antiretroviral medication primarily used in the treatment of HIV-1 infection. As the first integrase strand transfer inhibitor (INSTI), it functions by inhibiting the integrase enzyme, which is crucial for the viral replication process. This article explores the biological activity of raltegravir potassium, including its pharmacokinetics, mechanisms of action, efficacy in clinical studies, and safety profile.
Raltegravir inhibits the strand transfer activity of the HIV integrase enzyme. By doing so, it prevents the integration of viral DNA into the host cell genome, thereby blocking the replication cycle of HIV-1. This mechanism is vital for managing HIV infections, especially in patients with strains resistant to other antiretroviral therapies .
Pharmacokinetics
Absorption and Distribution:
- Raltegravir is rapidly absorbed after oral administration, with peak plasma concentrations occurring approximately 1 to 4 hours post-dose.
- It has a high plasma protein binding rate (approximately 83%) and shows extensive distribution throughout the body, with significant concentrations found in gastrointestinal organs and excretion pathways .
Metabolism:
- The primary metabolic pathway for raltegravir involves glucuronidation, primarily mediated by UGT1A1, with minor contributions from UGT1A9 and UGT1A3. This metabolic pathway results in a major metabolite that is less pharmacologically active than the parent compound .
Excretion:
- Raltegravir is excreted mainly through feces and urine. Studies have shown that it crosses the placenta and is present in breast milk, indicating potential implications for pregnant or lactating individuals .
Efficacy in Clinical Studies
Raltegravir has been evaluated in multiple clinical trials demonstrating its effectiveness in reducing viral loads and increasing CD4 cell counts among HIV-infected patients.
Key Findings from Clinical Trials:
- BENCHMRK Studies: In these randomized trials involving treatment-experienced patients, raltegravir showed a significant reduction in viral load compared to placebo. At week 156, 51% of patients on raltegravir achieved viral loads under 50 copies/mL versus only 22% in the placebo group .
| Study Duration | Raltegravir Group (%) | Placebo Group (%) |
|---|---|---|
| Week 156 | 51% < 50 copies/mL | 22% < 50 copies/mL |
| Week 240 | 42% < 50 copies/mL | - |
- Pediatric Studies: In trials involving children aged 2 years and older, raltegravir demonstrated a virologic success rate of approximately 53% at week 24 among treatment-experienced subjects. This indicates its efficacy across different age groups and treatment histories .
Safety Profile
Raltegravir is generally well-tolerated with a low incidence of severe adverse effects. Common side effects include nausea, headache, and fatigue. Importantly, it has a low potential for drug-drug interactions due to its unique metabolic pathway that does not involve cytochrome P450 enzymes .
Toxicity Studies:
属性
IUPAC Name |
potassium;4-[(4-fluorophenyl)methylcarbamoyl]-1-methyl-2-[2-[(5-methyl-1,3,4-oxadiazole-2-carbonyl)amino]propan-2-yl]-6-oxopyrimidin-5-olate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C20H21FN6O5.K/c1-10-25-26-17(32-10)16(30)24-20(2,3)19-23-13(14(28)18(31)27(19)4)15(29)22-9-11-5-7-12(21)8-6-11;/h5-8,28H,9H2,1-4H3,(H,22,29)(H,24,30);/q;+1/p-1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
IFUKBHBISRAZTF-UHFFFAOYSA-M |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=NN=C(O1)C(=O)NC(C)(C)C2=NC(=C(C(=O)N2C)[O-])C(=O)NCC3=CC=C(C=C3)F.[K+] |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C20H20FKN6O5 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID501007339 |
Source
|
| Record name | Potassium 4-[{[(4-fluorophenyl)methyl]imino}(hydroxy)methyl]-1-methyl-2-{2-[(5-methyl-1,3,4-oxadiazole-2-carbonyl)amino]propan-2-yl}-6-oxo-1,6-dihydropyrimidin-5-olate | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID501007339 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
482.5 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
871038-72-1 |
Source
|
| Record name | Raltegravir potassium [USAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0871038721 | |
| 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 | Potassium 4-[{[(4-fluorophenyl)methyl]imino}(hydroxy)methyl]-1-methyl-2-{2-[(5-methyl-1,3,4-oxadiazole-2-carbonyl)amino]propan-2-yl}-6-oxo-1,6-dihydropyrimidin-5-olate | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID501007339 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | potassium;4-[(4-fluorophenyl)methylcarbamoyl]-1-methyl-2-[2-[(5 methyl-1,3,4oxadiazole-2-carbonyl)amino]propan-2-yl]-6 oxopyrimidin-5-olate | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | RALTEGRAVIR POTASSIUM | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/43Y000U234 | |
| 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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Retrosynthesis Analysis
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