Valganciclovir
説明
バルガンシクロビルは、主にサイトメガロウイルス感染症の治療に使用される抗ウイルス薬であり、特に後天性免疫不全症候群（エイズ）患者や臓器移植後の患者など、免疫不全状態の患者に用いられます . これはガンシクロビルのL-バリルエステルであり、プロドラッグとして作用します。これは、投与後にその活性型であるガンシクロビルに変換されることを意味します . バルガンシクロビルは、ウイルスDNA合成を阻害することでサイトメガロウイルスの蔓延を阻止する有効性で知られています .
2. 製法
合成ルートと反応条件： バルガンシクロビルは、ガンシクロビルをL-バリンでエステル化するという複数段階のプロセスによって合成されます。 合成は、ガンシクロビルの保護から始まり、ジシクロヘキシルカルボジイミドや4-ジメチルアミノピリジンなどの試薬を用いてL-バリンでエステル化されます . 最終生成物は、脱保護と精製工程を経て得られます .
工業生産方法： バルガンシクロビルの工業生産は、同様の合成ルートを大規模に行います。 このプロセスには、精製と品質管理に高性能液体クロマトグラフィーを使用することが含まれます . 生産は、厳格な製薬基準に従って、高い収率と純度を確保するように最適化されています .
3. 化学反応解析
反応の種類： バルガンシクロビルは加水分解を受けて、活性型であるガンシクロビルに変換されます . この加水分解は、腸および肝臓エステラーゼによって促進されます . この化合物は、生理的条件下では、有意な酸化または還元反応を起こしません。
一般的な試薬と条件： バルガンシクロビルからガンシクロビルへの加水分解は、肝臓と腸に存在するエステラーゼによって触媒されます . この変換には、追加の試薬は必要ありません。
生成される主な生成物： バルガンシクロビルの加水分解によって生成される主要な生成物は、ガンシクロビルであり、これは活性な抗ウイルス薬です .
4. 科学研究への応用
バルガンシクロビルは、特に医学とウイルス学の分野において、科学研究において幅広い応用範囲を持っています。 これは、免疫不全患者のサイトメガロウイルス感染症の治療と予防に広く使用されています . さらに、バルガンシクロビルは、他のウイルス感染症や特定の種類の癌の治療における潜在的な用途について研究されています . 研究によると、バルガンシクロビルは、追加療法として使用した場合、再発性膠芽腫患者の生存率を向上させる可能性があります .
作用機序
生化学分析
Biochemical Properties
Valganciclovir plays a crucial role in biochemical reactions by inhibiting viral DNA synthesis. Upon administration, this compound is rapidly converted to Ganciclovir by intestinal and hepatic esterases . Ganciclovir then undergoes phosphorylation by viral protein kinase UL97 and subsequently by cellular kinases to form Ganciclovir triphosphate . This triphosphate form inhibits viral DNA polymerase, thereby preventing viral DNA replication . This compound interacts with enzymes such as viral protein kinase UL97 and cellular kinases, which are essential for its activation and antiviral activity .
Cellular Effects
This compound exerts significant effects on various cell types, particularly those infected with cytomegalovirus. It inhibits viral replication within infected cells, thereby reducing viral load and preventing the spread of infection . This compound influences cell function by interfering with cell signaling pathways involved in viral replication and gene expression . Additionally, it impacts cellular metabolism by inhibiting the synthesis of viral DNA, which is crucial for viral proliferation .
Molecular Mechanism
The molecular mechanism of this compound involves its conversion to Ganciclovir, which is then phosphorylated to its active triphosphate form . Ganciclovir triphosphate competes with deoxyguanosine triphosphate for incorporation into viral DNA by viral DNA polymerase . Once incorporated, it acts as a chain terminator, preventing further elongation of the viral DNA strand . This inhibition of viral DNA synthesis is the primary mechanism by which this compound exerts its antiviral effects .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of this compound have been observed to change over time. The stability of this compound is influenced by factors such as pH and temperature, with degradation occurring under extreme conditions . Long-term studies have shown that this compound maintains its antiviral activity over extended periods, although its efficacy may decrease with prolonged exposure . In vitro and in vivo studies have demonstrated that this compound effectively reduces viral load and prevents viral replication over time .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models. At therapeutic doses, this compound effectively inhibits viral replication and reduces viral load without causing significant toxicity . At higher doses, this compound can cause adverse effects such as bone marrow suppression and renal toxicity . Threshold effects have been observed, with higher doses leading to increased toxicity and reduced efficacy .
Metabolic Pathways
This compound is metabolized primarily in the liver and intestines, where it is converted to Ganciclovir by esterases . Ganciclovir is then phosphorylated by viral protein kinase UL97 and cellular kinases to form Ganciclovir triphosphate . This active metabolite inhibits viral DNA polymerase, preventing viral DNA synthesis . The metabolic pathways of this compound involve interactions with enzymes such as esterases, viral protein kinase UL97, and cellular kinases .
Transport and Distribution
This compound is transported and distributed within cells and tissues through various mechanisms. After oral administration, this compound is absorbed in the gastrointestinal tract and transported to the liver, where it is converted to Ganciclovir . Ganciclovir is then distributed to various tissues, including the kidneys, liver, and spleen . Transporters and binding proteins play a role in the distribution and localization of this compound within cells .
Subcellular Localization
The subcellular localization of this compound and its active metabolite, Ganciclovir triphosphate, is primarily within the nucleus of infected cells . This localization is crucial for its antiviral activity, as it allows for the inhibition of viral DNA synthesis within the nucleus . Targeting signals and post-translational modifications may influence the localization and activity of this compound within specific cellular compartments .
準備方法
Synthetic Routes and Reaction Conditions: Valganciclovir is synthesized through a multi-step process involving the esterification of ganciclovir with L-valine. The synthesis begins with the protection of ganciclovir, followed by esterification with L-valine using reagents such as dicyclohexylcarbodiimide and 4-dimethylaminopyridine . The final product is obtained through deprotection and purification steps .
Industrial Production Methods: Industrial production of this compound involves similar synthetic routes but on a larger scale. The process includes the use of high-performance liquid chromatography for purification and quality control . The production is optimized to ensure high yield and purity, adhering to stringent pharmaceutical standards .
化学反応の分析
Types of Reactions: Valganciclovir undergoes hydrolysis to convert into its active form, ganciclovir . This hydrolysis is facilitated by intestinal and hepatic esterases . The compound does not undergo significant oxidation or reduction reactions under physiological conditions.
Common Reagents and Conditions: The hydrolysis of this compound to ganciclovir is catalyzed by esterases present in the liver and intestines . No additional reagents are required for this conversion.
Major Products Formed: The primary product formed from the hydrolysis of this compound is ganciclovir, which is the active antiviral agent .
科学的研究の応用
Valganciclovir has a wide range of applications in scientific research, particularly in the fields of medicine and virology. It is extensively used in the treatment and prevention of cytomegalovirus infections in immunocompromised patients . Additionally, this compound has been investigated for its potential use in treating other viral infections and certain types of cancer . Research has shown that this compound can improve survival rates in patients with recurrent glioblastoma when used as an add-on therapy .
類似化合物との比較
バルガンシクロビルは、バラシクロビルやアシクロビルなどの他の抗ウイルス薬と比較されることがよくあります。 これらの3つの化合物はすべてヌクレオシドアナログですが、バルガンシクロビルは、サイトメガロウイルスに対してより幅広い活性を示すガンシクロビルに迅速に変換されるという点でユニークです . バラシクロビルとアシクロビルは、主に単純ヘルペスウイルス感染症の治療に使用され、薬物動態が異なります .
類似化合物:
ガンシクロビル: バルガンシクロビルの活性型であり、サイトメガロウイルス感染症の治療に使用されます.
バラシクロビル: アシクロビルに変換される抗ウイルスプロドラッグであり、単純ヘルペスウイルス感染症の治療に使用されます.
バルガンシクロビルは、サイトメガロウイルス感染症の治療における有効性と経口投与が可能であることから、長期治療に便利な選択肢となっています .
特性
| Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV in cell culture and in vivo. In CMV-infected cells ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly (half-life 18 hours). As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of the viral DNA polymerase, pUL54, synthesis by ganciclovir triphosphate. | |
CAS番号 |
175865-60-8 |
分子式 |
C14H22N6O5 |
分子量 |
354.36 g/mol |
IUPAC名 |
[2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]-3-hydroxypropyl] 2-amino-3-methylbutanoate |
InChI |
InChI=1S/C14H22N6O5/c1-7(2)9(15)13(23)24-4-8(3-21)25-6-20-5-17-10-11(20)18-14(16)19-12(10)22/h5,7-9,21H,3-4,6,15H2,1-2H3,(H3,16,18,19,22) |
InChIキー |
WPVFJKSGQUFQAP-UHFFFAOYSA-N |
SMILES |
CC(C)C(C(=O)OCC(CO)OCN1C=NC2=C1N=C(NC2=O)N)N |
異性体SMILES |
CC(C)C(C(=O)OC[C@H](CO)OCN1C=NC2=C1N=C(NC2=O)N)N |
正規SMILES |
CC(C)C(C(=O)OCC(CO)OCN1C=NC2=C1N=C(NC2=O)N)N |
物理的記述 |
Solid |
純度 |
> 95% |
数量 |
Milligrams-Grams |
溶解性 |
4.79e+00 g/L |
同義語 |
5-Amino-3-[1-(hydroxymethyl)-2-(L-valyloxy)ethoxymethyl]-6,7- dihydro-3H-imidazo[4,5-d]pyrimidin-7-one; (2S)-2-((2-AMino-6-oxo-1H-purin-9(6H)-yl)Methoxy)-3-hydroxypropyl 2-aMino-3-Methylbutanoate |
製品の起源 |
United States |
Q1: How does Valganciclovir exert its antiviral effect?
A: this compound itself is a prodrug, rapidly hydrolyzed in vivo to its active form, Ganciclovir. [] Ganciclovir is a nucleoside analogue that inhibits viral DNA polymerase. [, , , ] Once phosphorylated by viral and cellular kinases, it competitively inhibits CMV DNA polymerase, effectively halting viral DNA synthesis. [, , , ]
Q2: How does Ganciclovir's inhibition of DNA polymerase differ from that of other antiviral agents?
A: Unlike acyclovir, which requires viral thymidine kinase for initial phosphorylation, Ganciclovir can be phosphorylated by cellular kinases, making it effective against a broader range of CMV strains. []
Q3: What are the downstream effects of Ganciclovir inhibiting CMV DNA polymerase?
A: By blocking viral DNA synthesis, Ganciclovir effectively halts CMV replication, preventing further spread of the virus and allowing the immune system to control the infection. [, , ]
Q4: What is the molecular formula and weight of this compound?
A4: The molecular formula of this compound is C20H28N10O7, and its molecular weight is 504.5 g/mol.
Q5: How stable is this compound in solution?
A: While this compound has good oral bioavailability, it can undergo degradation in aqueous solutions. []
Q6: How is this compound absorbed and metabolized in the body?
A: this compound exhibits excellent oral bioavailability (around 60%) due to its rapid hydrolysis to Ganciclovir. [, ] This is significantly higher than the bioavailability of oral Ganciclovir. [, , ]
Q7: Does renal function affect this compound dosing?
A: Yes, this compound dosage adjustments are crucial for patients with renal impairment, as its clearance is primarily renal. [, , , ] Dosage adjustments based on estimated creatinine clearance are frequently necessary, especially in the context of solid organ transplantation. [, ]
Q8: Has the pharmacokinetic profile of this compound been studied in specific populations, like children?
A: Yes, research indicates the need for careful dose individualization in children, as younger patients and those with lower body surface area may exhibit significantly lower Ganciclovir exposure. [, ]
Q9: Is this compound effective for both prophylaxis and treatment of CMV infection?
A: Research supports the use of this compound for both the prevention and treatment of CMV infection in various clinical settings, including solid organ transplant recipients and individuals with AIDS. [, , , , , , ]
Q10: What is the evidence supporting this compound's efficacy in preventing CMV retinitis?
A: Clinical trials have demonstrated that oral this compound is as effective as intravenous Ganciclovir for both induction and maintenance treatment of CMV retinitis in patients with AIDS. [, ]
Q11: How does the efficacy of this compound prophylaxis compare to preemptive therapy in kidney transplant recipients?
A: While both strategies can effectively prevent CMV disease, studies suggest that this compound prophylaxis may be associated with a lower incidence of CMV infection and disease, particularly in donor-positive/recipient-positive patients. [, , ]
Q12: Does resistance to this compound develop?
A: Resistance to Ganciclovir, and therefore this compound, can emerge, primarily through mutations in the UL97 gene encoding the viral kinase that phosphorylates Ganciclovir. [, , ]
Q13: Are there specific drug delivery strategies being explored for this compound?
A: While the provided research primarily focuses on oral administration, the development of targeted drug delivery systems could potentially enhance its efficacy and minimize off-target effects. []
Q14: What are some important research tools and resources for studying this compound?
A14: Key resources include:
- In vitro cell culture models: These allow for investigating the antiviral activity of this compound and studying resistance mechanisms. []
- Animal models: These are crucial for preclinical evaluation of efficacy and safety. [, ]
- Clinical trial databases: These provide valuable data on the efficacy and safety of this compound in various patient populations. [, , , , , , , ]
- Pharmacokinetic modeling software: This aids in understanding the absorption, distribution, metabolism, and excretion of this compound, especially in specific populations. []
試験管内研究製品の免責事項と情報
BenchChemで提示されるすべての記事および製品情報は、情報提供を目的としています。BenchChemで購入可能な製品は、生体外研究のために特別に設計されています。生体外研究は、ラテン語の "in glass" に由来し、生物体の外で行われる実験を指します。これらの製品は医薬品または薬として分類されておらず、FDAから任何の医療状態、病気、または疾患の予防、治療、または治癒のために承認されていません。これらの製品を人間または動物に体内に導入する形態は、法律により厳格に禁止されています。これらのガイドラインに従うことは、研究と実験において法的および倫理的な基準の遵守を確実にするために重要です。
