阿巴卡韦
描述
阿巴卡韦是一种合成的碳环核苷类似物逆转录酶抑制剂，主要用于治疗人类免疫缺陷病毒 (HIV) 和获得性免疫缺陷综合征 (AIDS)。它以商品名齐格恩等上市。 阿巴卡韦通常与其他抗逆转录病毒药物联合使用，不建议单独使用 . 它因其能够通过靶向逆转录酶来抑制 HIV 的复制而闻名，逆转录酶对于病毒的复制过程至关重要 .
科学研究应用
Clinical Efficacy in HIV Treatment
Abacavir is FDA-approved for use in adults and children over three months old as part of combination antiretroviral therapy (ART). It is often administered alongside other agents such as lamivudine and dolutegravir.
Clinical Trials and Outcomes
- A pivotal study compared abacavir with zidovudine combined with lamivudine. At week 48, 70% of patients on abacavir achieved plasma HIV-1 RNA levels of ≤50 copies/mL, similar to the zidovudine group (69%) .
- The median increase in CD4+ cell counts was significantly higher in the abacavir group (209 cells/mm³) compared to the zidovudine group (155 cells/mm³), indicating a robust immunological response .
Pharmacokinetics
Abacavir exhibits a two-compartment pharmacokinetic model with high oral bioavailability. Key pharmacokinetic parameters include:
- Clearance : Increased from a mean of 3.33 to 5.86 L/h/7 kg from day 1 to day 14 in severely malnourished children .
- Central Nervous System Penetration : Studies indicate that abacavir penetrates the central nervous system effectively, with a CSF/plasma concentration ratio of approximately 31% to 44% .
Safety Profile and Side Effects
While abacavir is generally well-tolerated, it has been associated with hypersensitivity reactions, particularly in individuals with the HLA-B*57:01 allele. This genetic predisposition can lead to severe allergic reactions upon exposure to the drug.
Cardiovascular Risks
Recent analyses have linked abacavir use to an increased risk of major adverse cardiovascular events (MACE). A meta-analysis indicated that current or past use of abacavir may elevate cardiovascular disease risk among HIV patients .
Off-Label Uses
Abacavir has been explored for various off-label applications, including:
- HIV Treatment in Special Populations : Research has demonstrated its efficacy in severely malnourished children, showing that WHO weight-band dosing recommendations are appropriate for this demographic .
- Potential Role in Cancer Therapy : Emerging studies are investigating the immunomodulatory effects of abacavir that may enhance responses to cancer therapies.
Case Studies and Research Findings
Several studies have documented the diverse applications and outcomes associated with abacavir:
作用机制
阿巴卡韦在细胞内被转化为其活性代谢物碳环鸟苷三磷酸。这种代谢物是脱氧鸟苷-5'-三磷酸 (dGTP) 的类似物，与 HIV 逆转录酶竞争，将自身整合到病毒 DNA 中。 一旦整合进去，它就会作为链终止剂，阻止病毒 DNA 的延伸，从而抑制病毒的复制 .
类似化合物：
拉米夫定： 另一种与阿巴卡韦联合使用的核苷逆转录酶抑制剂。
齐多夫定： 一种较早的核苷逆转录酶抑制剂，其作用机制相似。
替诺福韦： 具有不同化学结构但具有类似抗病毒活性的核苷酸逆转录酶抑制剂。
比较：
独特性： 阿巴卡韦作为一种碳环核苷类似物的结构是独一无二的。它具有独特的环丙基胺基团，使其与其他核苷类似物区分开来。
准备方法
合成路线和反应条件： 阿巴卡韦的合成涉及多个步骤，从合适的二卤氨基嘧啶化合物开始。关键步骤包括：
与氨基醇反应： 二卤氨基嘧啶与氨基醇反应形成中间体化合物。
环化： 该中间体进行环化形成关键中间体。
引入环丙基胺： 中间体的氯原子被环丙基胺取代，生成阿巴卡韦游离碱.
工业生产方法： 阿巴卡韦的工业生产通常涉及优化反应条件，以确保高产率和纯度。这包括控制温度、pH 值，以及使用特定的催化剂来促进反应。 该过程还可能涉及纯化步骤，如结晶和色谱法，以分离最终产物 .
反应类型：
常用试剂和条件：
氧化： 过氧化氢、铂电极、硼掺杂金刚石电极。
取代： 环丙基胺、各种溶剂和催化剂。
主要产物：
相似化合物的比较
Lamivudine: Another nucleoside reverse transcriptase inhibitor used in combination with abacavir.
Zidovudine: An older nucleoside reverse transcriptase inhibitor with a similar mechanism of action.
Tenofovir: A nucleotide reverse transcriptase inhibitor with a different chemical structure but similar antiviral activity.
Comparison:
Uniqueness: Abacavir is unique in its structure as a carbocyclic nucleoside analog. It has a distinct cyclopropylamine group that differentiates it from other nucleoside analogs.
Safety Profile: Abacavir has a well-documented safety profile, though it is associated with a risk of hypersensitivity reactions and potential cardiovascular risks.
生物活性
Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) primarily used in the treatment of HIV infection. Its biological activity is characterized by its mechanism of action, pharmacokinetics, therapeutic efficacy, safety profile, and potential side effects, including hypersensitivity reactions. This article synthesizes findings from various studies and case reports to provide a comprehensive overview of abacavir's biological activity.
Abacavir is metabolized intracellularly to its active form, carbovir triphosphate (CBV-TP), which competes with natural deoxyguanosine triphosphate for incorporation into viral DNA. This incorporation results in chain termination during reverse transcription, effectively inhibiting viral replication. Abacavir has demonstrated potency against HIV strains resistant to other NRTIs, making it a valuable option in antiretroviral therapy (ART) regimens .
Pharmacokinetics
The pharmacokinetic profile of abacavir reveals significant insights into its absorption, distribution, metabolism, and excretion:
- Absorption : Abacavir is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1.5 to 2 hours.
- Distribution : The drug penetrates the central nervous system (CNS) effectively, with cerebrospinal fluid (CSF) concentrations significantly exceeding the inhibitory concentration for HIV .
- Metabolism : Abacavir is primarily metabolized by the liver through non-CYP450 pathways, reducing the risk of drug-drug interactions commonly associated with other antiretrovirals .
- Excretion : The drug is eliminated mainly via renal clearance, with minimal hepatic metabolism .
Efficacy in Clinical Studies
Abacavir has been evaluated in numerous clinical trials demonstrating its efficacy as part of ART regimens:
- In a comparative study with zidovudine and lamivudine, abacavir showed non-inferior efficacy in maintaining viral suppression (70% vs. 69% at week 48) and a favorable CD4+ cell response (209 cells/mm³ vs. 155 cells/mm³) .
- A meta-analysis indicated that viral suppression rates ranged from 50% to 70% at six months and from 57% to 78% at twelve months in pediatric populations treated with abacavir .
Safety Profile and Hypersensitivity Reactions
While abacavir is generally well-tolerated, it is associated with hypersensitivity reactions (HSRs) in a subset of patients. The incidence of HSRs can be influenced by genetic factors such as HLA-B*5701 status:
- Case Study Example : A patient developed gastrointestinal symptoms and fever within days of initiating therapy with abacavir. Upon discontinuation, symptoms resolved rapidly, indicating a probable hypersensitivity reaction .
Table 1: Summary of Abacavir Hypersensitivity Reactions
| Study/Case | Population | Symptoms | Outcomes |
|---|---|---|---|
| Case #3 | Adult male | Vomiting, diarrhea, fever | Symptoms resolved post-discontinuation |
| Patel et al. (2020) | Pediatric patients | Variable symptoms | Incidence rate varied from 0% to 5.49% |
Research Findings on Oncogenic Activity
Recent studies have also explored the potential oncogenic effects of abacavir. Research indicates that abacavir can activate oncogenic transcription factors in gastric cancer cells, suggesting a complex role beyond its antiviral activity:
属性
IUPAC Name |
[4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methanol |
Source
|
|---|---|---|
| Details | Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C14H18N6O/c15-14-18-12(17-9-2-3-9)11-13(19-14)20(7-16-11)10-4-1-8(5-10)6-21/h1,4,7-10,21H,2-3,5-6H2,(H3,15,17,18,19) |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
MCGSCOLBFJQGHM-UHFFFAOYSA-N |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1CC1NC2=C3C(=NC(=N2)N)N(C=N3)C4CC(C=C4)CO |
Source
|
| Details | Computed by OEChem 2.3.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C14H18N6O |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID20861337 |
Source
|
| Record name | 4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID20861337 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
286.33 g/mol |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
136470-78-5, 914348-29-1 |
Source
|
| Record name | NSC742406 | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=742406 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | 4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID20861337 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
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
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