Empagliflozin
描述
恩格列净是一种口服药物，主要用于治疗2型糖尿病。它属于一类称为钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂的药物。通过抑制SGLT2，恩格列净减少肾脏对葡萄糖的重吸收，导致尿中葡萄糖排泄增加。 这有助于降低2型糖尿病患者的血糖水平 .
准备方法
合成路线和反应条件： 恩格列净通过涉及多个关键中间体的多步合成过程合成。一种常见的合成路线包括以下步骤：
中间体I的形成： 初始步骤涉及4-氯-3-(4-(四氢呋喃-3-基氧基)苄基)苯基与合适的糖基供体反应，形成中间体I。
中间体II的形成： 中间体I经历进一步的反应，包括保护和脱保护步骤，以生成中间体II。
工业生产方法： 恩格列净的工业生产通常涉及使用优化反应条件的大规模合成，以确保高产率和纯度。该过程包括：
回流： 反应混合物回流以促进所需产物的形成。
化学反应分析
反应类型： 恩格列净经历各种化学反应，包括：
常见试剂和条件：
氧化降解： 过氧化氢或其他氧化剂等试剂可以诱导氧化降解。
主要形成的产物：
氧化降解产物： 根据所用条件和试剂的不同，可能会形成各种氧化产物。
水解产物： 水解会导致较小片段和降解产物的形成.
科学研究应用
Empagliflozin is a relatively new drug that inhibits the sodium–glucose cotransporter 2 (SGLT2), increasing urinary glucose excretion . Originally used to induce a hypoglycemic effect in patients with type 2 diabetes mellitus (T2DM), this compound has demonstrated other beneficial effects, including nephroprotection and as a breakthrough in treating heart failure (HF) . Studies have shown benefits in patients with and without T2DM .
Scientific Research Applications
A study evaluated this compound initiated in-hospital for acute heart failure . The primary outcome was clinical benefit, assessed using a hierarchical composite of death from any cause, the number of heart failure events, time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days . More patients treated with this compound had clinical benefit compared with placebo . Clinical benefit was seen for both acute de novo and decompensated chronic heart failure and regardless of ejection fraction or diabetes status . this compound was well tolerated, with fewer serious adverse events than placebo . These results extend and complement those of EMPEROR-Reduced and EMPEROR-Preserved by focusing on patients hospitalized for acute heart failure across the range of ejection fraction .
Renal Protection: this compound significantly reduces the relative risk of developing or worsening nephropathy by 39% compared to placebo . The relative risk reduction for progression to macroalbuminuria between the this compound and placebo groups was 38% . The risk of doubling plasma creatinine levels was reduced by 44% in the this compound group, and the relative risk of starting renal replacement therapy (RRT) was significantly 55% lower .
Alzheimer's Disease: A five-drug combination consisting of Tofacitinib, Niraparib, Baricitinib, this compound, and Doxercalciferol can serve as a promising drug combination for AD treatment . this compound, an SGLT2 inhibitor, regulates the insulin signaling pathway linking diabetes and AD . this compound can target EGFR in the MAPK, FOXO, and Rap1 signaling pathways via SLC5A1 .
Improved Cardiac Function: this compound administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality . this compound significantly ameliorated adverse LV remodeling, decreased LV volumes and LV hypertrophy, reduced neurohormonal activation, and improved cardiac systolic function compared with the control group . Moreover, this compound also improved diastolic function in this HFrEF model .
Improved Clinical Stability: this compound reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction . this compound reduced the total number of heart failure hospitalizations that required intensive care and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention . Patients assigned to this compound were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up .
Data Table
作用机制
恩格列净通过抑制肾脏中的钠-葡萄糖协同转运蛋白2（SGLT2）发挥作用。这种抑制减少了肾小球滤液中葡萄糖的重吸收，导致尿中葡萄糖排泄增加。血糖水平的降低有助于控制2型糖尿病。 此外，恩格列净已被证明具有心脏保护作用和肾脏保护作用，这些作用被认为是通过减少氧化应激和改善内皮功能等机制介导的 .
相似化合物的比较
恩格列净属于SGLT2抑制剂类药物。该类中的其他类似化合物包括：
达格列净： 该化合物也用于治疗2型糖尿病，并已获准用于治疗心力衰竭.
依格列净： 另一种作用机制类似但药代动力学特性不同的SGLT2抑制剂.
恩格列净的独特之处： 恩格列净在SGLT2上具有高度选择性，而对SGLT1的选择性较低，这有助于其疗效和安全性。 它还已被证明具有显著的心血管和肾脏益处，使其成为患有2型糖尿病和合并症患者的宝贵选择 .
生物活性
Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor primarily used in the management of type 2 diabetes mellitus (T2DM). Its biological activity extends beyond glycemic control, showing significant cardiovascular benefits and effects on cardiac metabolism. This article reviews the biological activity of this compound, supported by recent studies, clinical trials, and case studies.
This compound works by inhibiting the SGLT2 protein in the kidneys, leading to reduced glucose reabsorption and increased glucose excretion. This mechanism not only lowers blood glucose levels but also has secondary effects on cardiovascular health.
- Cardiac Energy Metabolism : Recent studies indicate that this compound enhances cardiac energy status by increasing ATP levels in both cytosolic and mitochondrial compartments within cardiomyocytes. In a study involving db/db mice, this compound treatment resulted in a significant increase in mitochondrial ATP levels, which was associated with improved cardiac function during ischemic conditions .
- Cardioprotection : this compound has been shown to provide cardioprotective effects, particularly in models of heart failure. It improves recovery capacity in ischemic-reperfusion scenarios and maintains ATP levels during stress conditions .
Clinical Evidence
This compound's efficacy has been validated through various clinical trials:
- EMPULSE Trial : This double-blind trial evaluated this compound in patients hospitalized for acute heart failure. Results indicated that this compound significantly improved clinical outcomes compared to placebo, with a stratified win ratio of 1.36 (p = 0.0054), demonstrating its potential benefits even when initiated during hospitalization .
- Long-term Cardiovascular Outcomes : In patients with chronic heart failure, this compound reduced the risk of cardiovascular death and heart failure hospitalization. The drug was well tolerated, with serious adverse events occurring less frequently than in the placebo group .
Case Studies
Several case studies highlight the biological activity of this compound:
- Case Study on Cardiac Remodeling : A study focused on patients with T2DM and coronary artery disease found that this compound treatment led to a reduction in left ventricular mass over time, suggesting beneficial remodeling effects on the heart .
- Impact on Diabetic Patients : Research involving diabetic patients showed that this compound effectively reduced fasting plasma glucose and glycated hemoglobin levels while also improving markers of cardiovascular health, such as blood pressure and weight management .
Summary of Findings
The following table summarizes key findings from recent studies regarding the biological activity of this compound:
属性
IUPAC Name |
(2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C23H27ClO7/c24-18-6-3-14(23-22(28)21(27)20(26)19(11-25)31-23)10-15(18)9-13-1-4-16(5-2-13)30-17-7-8-29-12-17/h1-6,10,17,19-23,25-28H,7-9,11-12H2/t17-,19+,20+,21-,22+,23-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
OBWASQILIWPZMG-QZMOQZSNSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1COCC1OC2=CC=C(C=C2)CC3=C(C=CC(=C3)C4C(C(C(C(O4)CO)O)O)O)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
C1COC[C@H]1OC2=CC=C(C=C2)CC3=C(C=CC(=C3)[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C23H27ClO7 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID601026093 |
Source
|
| Record name | Empagliflozin | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID601026093 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
450.9 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
The vast majority of glucose filtered through the glomerulus is reabsorbed within the proximal tubule, primarily via SGLT2 (sodium-glucose linked co-transporter-2) which is responsible for ~90% of the total glucose reabsorption within the kidneys. Na+/K+-ATPase on the basolateral membrane of proximal tubular cells utilize ATP to actively pump Na+ ions into the interstitium surrounding the tubule, establishing a Na+ gradient within the tubular cell. SGLT2 on the apical membrane of these cells then utilize this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, thereby reabsorbing glucose back into the blood – inhibiting this co-transport, then, allows for a marked increase in glucosuria and decrease in blood glucose levels. Empagliflozin is a potent inhibitor of renal SGLT2 transporters located in the proximal tubules of the kidneys and works to lower blood glucose levels via an increase in glucosuria. Empagliflozin also appears to exert cardiovascular benefits - specifically in the prevention of heart failure - independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na+/H+ exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines. |
Source
|
| Record name | Empagliflozin | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09038 | |
| 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. |
864070-44-0 |
Source
|
| Record name | Empagliflozin | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=864070-44-0 | |
| 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 | Empagliflozin [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0864070440 | |
| 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 | Empagliflozin | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09038 | |
| 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 | Empagliflozin | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID601026093 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol | |
| 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 | EMPAGLIFLOZIN | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/HDC1R2M35U | |
| 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. | |
Retrosynthesis Analysis
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| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
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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。
