比索洛尔
概述
描述
比索洛尔是一种心脏选择性β1受体阻滞剂，通常称为β受体阻滞剂。它主要用于治疗心血管疾病，如高血压、心绞痛和心力衰竭。 比索洛尔通过降低心率和收缩力起作用，从而降低血压并减少心脏的氧气需求 .
科学研究应用
比索洛尔在科学研究中有广泛的应用：
化学： 用作研究β受体阻滞剂及其与各种受体相互作用的模型化合物。
生物学： 研究其对细胞过程的影响及其与β肾上腺素受体的相互作用。
医学： 广泛用于临床试验，以评估其治疗心血管疾病的疗效。
作用机制
比索洛尔通过选择性阻断心脏中的β1肾上腺素受体发挥作用。这种作用降低了心率和收缩力，导致心输出量和血压下降。 参与其中的分子靶标包括β1肾上腺素受体，它是交感神经系统的一部分 .
生化分析
Biochemical Properties
Bisoprolol plays a significant role in biochemical reactions by selectively inhibiting beta-1 adrenergic receptors. These receptors are primarily found in the heart muscle cells and heart conduction tissue . By blocking these receptors, bisoprolol reduces the effects of catecholamines (adrenaline and noradrenaline), which are responsible for increasing heart rate and contractility . This inhibition leads to a decrease in heart rate and myocardial oxygen demand, making bisoprolol effective in managing cardiovascular conditions .
Cellular Effects
Bisoprolol exerts various effects on different types of cells and cellular processes. In myocardial cells, bisoprolol reduces oxygen consumption by decreasing heart rate and contractility . This reduction in workload helps alleviate symptoms of angina and heart failure. Additionally, bisoprolol influences cell signaling pathways by blocking the beta-1 adrenergic receptors, which are involved in the sympathetic nervous system’s response to stress . This blockade results in decreased cyclic AMP (cAMP) levels and reduced activation of protein kinase A (PKA), ultimately leading to decreased phosphorylation of target proteins involved in cardiac contraction .
Molecular Mechanism
The molecular mechanism of bisoprolol involves its selective and competitive binding to beta-1 adrenergic receptors . By blocking these receptors, bisoprolol prevents the binding of catecholamines, thereby inhibiting the downstream signaling cascade that leads to increased heart rate and contractility . This competitive inhibition results in decreased activation of adenylate cyclase, reduced cAMP production, and subsequent inhibition of PKA activity . The overall effect is a reduction in myocardial oxygen demand and improved cardiac function .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of bisoprolol have been observed to change over time. Bisoprolol exhibits a long plasma-elimination half-life of approximately 10-12 hours, allowing for once-daily dosing . Studies have shown that bisoprolol maintains its efficacy over extended periods, with stable blood pressure control and heart rate reduction . Additionally, bisoprolol is metabolized in the liver and excreted by the kidneys, with no significant accumulation of metabolites . Long-term studies have demonstrated that bisoprolol remains effective and well-tolerated in managing cardiovascular conditions .
Dosage Effects in Animal Models
In animal models, the effects of bisoprolol vary with different dosages. Studies have shown that low to moderate doses of bisoprolol effectively reduce heart rate and blood pressure without causing significant adverse effects . At higher doses, bisoprolol may lead to bradycardia, hypotension, and other cardiovascular complications . Toxicity studies in animals have indicated that bisoprolol has a wide therapeutic window, with a low risk of severe toxicity at therapeutic doses .
Metabolic Pathways
Bisoprolol is metabolized through oxidative pathways in the liver, primarily by the cytochrome P450 enzymes CYP3A4 and CYP2D6 . Approximately 50% of the administered dose is metabolized to inactive metabolites, which are then excreted by the kidneys . The remaining 50% is excreted unchanged in the urine . Bisoprolol’s metabolism is not significantly affected by genetic polymorphisms, making it a reliable medication for a wide range of patients .
Transport and Distribution
Bisoprolol is rapidly absorbed after oral administration, with a bioavailability of over 90% . It is widely distributed throughout the body, with the highest concentrations found in the heart, liver, lungs, and saliva . Bisoprolol crosses the blood-brain barrier, although its central nervous system effects are minimal due to its high selectivity for beta-1 adrenergic receptors . The drug is approximately 30% bound to plasma proteins, which contributes to its distribution and elimination .
Subcellular Localization
At the subcellular level, bisoprolol primarily localizes to the plasma membrane, where it interacts with beta-1 adrenergic receptors . These receptors are part of the G protein-coupled receptor family and are involved in the regulation of cardiac function . Bisoprolol’s selective binding to these receptors inhibits the activation of downstream signaling pathways, leading to decreased cardiac contractility and heart rate . The drug’s localization to the plasma membrane ensures its targeted action on cardiac cells, minimizing off-target effects .
准备方法
比索洛尔可以通过多种方法合成。一种常见的合成路线是将4-异丙氧基乙氧基甲基苯酚与环氧氯丙烷反应，生成2-[4-(2-异丙氧基乙氧基)甲基]苯氧基甲基环氧乙烷。 然后将该中间体与异丙胺反应生成比索洛尔 . 工业生产方法通常涉及类似的步骤，但针对大规模生产进行了优化，确保高产率和纯度 .
化学反应分析
比索洛尔会发生各种化学反应，包括：
氧化： 比索洛尔可以氧化形成各种代谢物。
还原： 还原反应不太常见，但在特定条件下会发生。
取代： 比索洛尔可以发生取代反应，特别是涉及其酚基和胺基。
这些反应中常用的试剂包括过氧化氢等氧化剂和硼氢化钠等还原剂。 这些反应形成的主要产物通常是代谢物，这些代谢物要么被排泄，要么在体内被进一步代谢 .
相似化合物的比较
比索洛尔经常与其他β受体阻滞剂进行比较，如阿替洛尔、美托洛尔和普萘洛尔。 虽然所有这些化合物都具有相似的作用机制，但比索洛尔对β1肾上腺素受体的选择性很高，这降低了与β2受体阻滞相关的副作用的风险，例如支气管痉挛 .
类似化合物
- 阿替洛尔
- 美托洛尔
- 普萘洛尔
- 卡维地洛
- 拉贝洛尔
属性
IUPAC Name |
1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy]propan-2-ol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C18H31NO4/c1-14(2)19-11-17(20)13-23-18-7-5-16(6-8-18)12-21-9-10-22-15(3)4/h5-8,14-15,17,19-20H,9-13H2,1-4H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
VHYCDWMUTMEGQY-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)NCC(COC1=CC=C(C=C1)COCCOC(C)C)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C18H31NO4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID6022682 |
Source
|
| Record name | Bisoprolol | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6022682 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
325.4 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 | Bisoprolol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014750 | |
| 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. | |
Boiling Point |
445.0±45.0 |
Source
|
| Record name | Bisoprolol | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00612 | |
| 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) | |
Solubility |
7.07e-02 g/L |
Source
|
| Record name | Bisoprolol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014750 | |
| 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 |
Though the mechanism of action of bisoprolol has not been fully elucidated in hypertension, it is thought that therapeutic effects are achieved through the antagonism of β-1adrenoceptors to result in lower cardiac output. Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. When β1-receptors (located mainly in the heart) are activated by adrenergic neurotransmitters such as epinephrine, both the blood pressure and heart rate increase, leading to greater cardiovascular work, increasing the demand for oxygen. Bisoprolol reduces cardiac workload by decreasing contractility and the need for oxygen through competitive inhibition of β1-adrenergic receptors. Bisoprolol is also thought to reduce the output of renin in the kidneys, which normally increases blood pressure. Additionally, some central nervous system effects of bisoprolol may include diminishing sympathetic nervous system output from the brain, decreasing blood pressure and heart rate. |
Source
|
| Record name | Bisoprolol | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00612 | |
| 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. |
66722-44-9 |
Source
|
| Record name | Bisoprolol | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=66722-44-9 | |
| 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 | Bisoprolol [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0066722449 | |
| 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 | Bisoprolol | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00612 | |
| 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 | Bisoprolol | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6022682 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 2-Propanol, 1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino] | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.108.941 | |
| 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 | BISOPROLOL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/Y41JS2NL6U | |
| 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 | Bisoprolol | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8316 | |
| 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 | Bisoprolol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014750 | |
| 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. | |
Melting Point |
100-103, 100 °C |
Source
|
| Record name | Bisoprolol | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00612 | |
| 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 | Bisoprolol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014750 | |
| 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. | |
Synthesis routes and methods
Procedure details
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 bisoprolol exert its effects on the cardiovascular system?
A1: Bisoprolol is a highly selective β1-adrenergic receptor antagonist []. This means it primarily blocks the action of adrenaline and noradrenaline at the β1-adrenergic receptors found mainly in the heart. [, , ] By blocking these receptors, bisoprolol reduces heart rate, myocardial contractility, and ultimately lowers blood pressure. [, , ]
Q2: Does bisoprolol affect β2-adrenergic receptors?
A2: Bisoprolol exhibits high selectivity for β1-adrenergic receptors, demonstrating minimal effects on bronchial β2-adrenergic receptors at therapeutic doses. [, ] This selectivity makes it a preferred choice for treating hypertension in patients with asthma compared to less selective beta-blockers like atenolol. []
Q3: Are there any potential long-term benefits of bisoprolol beyond its immediate hemodynamic effects?
A3: Research suggests that bisoprolol might provide additional benefits by reducing oxidative stress and inflammation, particularly in the context of heart failure. [, ] Studies in animal models have shown that bisoprolol can improve cardiac function, reduce myocardial damage, and delay the progression of heart failure, potentially by attenuating oxidative stress and reducing the levels of inflammatory markers. []
Q4: What is the molecular formula and weight of bisoprolol?
A4: Bisoprolol has a molecular formula of C18H31NO4 and a molecular weight of 325.44 g/mol. This information is essential for researchers working on synthesizing, characterizing, and formulating bisoprolol for various applications.
Q5: What spectroscopic techniques are commonly used to characterize bisoprolol?
A5: Spectroscopic techniques like UV-Vis spectrophotometry are frequently employed for the analysis of bisoprolol. Bisoprolol exhibits maximum UV absorbance (λmax) at 208 nm. [] This property enables its detection and quantification using high-performance liquid chromatography (HPLC) coupled with UV detectors. [, ]
Q6: What is the pharmacokinetic profile of bisoprolol?
A6: Bisoprolol is well-absorbed after oral administration, reaching peak plasma concentrations within 2-4 hours. [, , ] It has a relatively long half-life of 10-12 hours, allowing for once-daily dosing. [, ] Bisoprolol is primarily metabolized in the liver and excreted in the urine. []
Q7: How do the pharmacokinetic properties of bisoprolol compare to other beta-blockers?
A7: Bisoprolol's longer half-life allows for once-daily dosing compared to other beta-blockers like atenolol, which requires twice-daily administration. [, , ] This difference in dosing frequency can influence patient adherence and potentially impact therapeutic outcomes.
Q8: What are the main clinical indications for bisoprolol?
A8: Bisoprolol is primarily used to treat hypertension, angina pectoris, and chronic heart failure. [, , , ] Its beneficial effects on heart rate, blood pressure, and myocardial oxygen consumption contribute to its efficacy in these conditions. [, , ]
Q9: How does bisoprolol compare to other beta-blockers in treating heart failure?
A10: Clinical trials like the Cardiac Insufficiency Bisoprolol Study (CIBIS) have shown that bisoprolol significantly improves symptoms and reduces mortality in patients with chronic heart failure. [, , ] While other beta-blockers like carvedilol and metoprolol are also effective, studies comparing their efficacy have yielded varying results. [, ]
Q10: What are the potential benefits of combining bisoprolol with other drugs in specific patient populations?
A11: Studies suggest that combining bisoprolol with other antihypertensive agents like amlodipine can significantly improve blood pressure control in patients who haven't responded well to monotherapy. [] Additionally, adding bisoprolol to standard treatment in heart failure patients with preserved ejection fraction has shown potential benefits in specific subgroups. []
Q11: What are some common side effects of bisoprolol?
A12: Although generally well-tolerated, bisoprolol can cause side effects like bradycardia (slow heart rate), fatigue, dizziness, and cold extremities. [, , ] These side effects are often dose-dependent and can be minimized by starting with a low dose and titrating it gradually based on patient response and tolerance. [, ]
Q12: Are there specific patient populations where bisoprolol use should be approached with caution?
A13: Bisoprolol should be used cautiously in patients with pre-existing bradycardia, heart block, or severe heart failure. [] Careful dose adjustments and close monitoring are crucial in these patients to minimize the risk of adverse events.
Q13: What analytical methods are commonly used to quantify bisoprolol in biological samples?
A14: High-performance liquid chromatography (HPLC) coupled with various detection methods, such as UV detection or mass spectrometry (MS), is widely employed to quantify bisoprolol in biological samples like plasma or cell lysates. [, , ] These methods offer high sensitivity and selectivity for accurate determination of bisoprolol concentrations.
Q14: Are there any specialized formulations of bisoprolol available?
A15: Aside from oral tablets, bisoprolol is also available as a transdermal patch. [] This formulation can provide more stable drug levels and potentially reduce certain side effects compared to oral administration. []
Q15: What are some areas for future research on bisoprolol?
A16: Further research is needed to optimize the use of bisoprolol in specific patient populations, such as those with chronic obstructive pulmonary disease (COPD) or elderly patients with hypertension and diabetes. [, ] Additionally, exploring the potential benefits of bisoprolol in delaying the progression of heart failure and reducing cardiovascular events warrants further investigation.
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