Empagliflozin

Synthetic Routes and Reaction Conditions: Empagliflozin is synthesized through a multi-step process involving several key intermediates. One common synthetic route involves the following steps:

Formation of Intermediate I: The initial step involves the reaction of 4-chloro-3-(4-(tetrahydrofuran-3-yloxy)benzyl)phenyl with a suitable glucosyl donor to form Intermediate I.

Formation of Intermediate II: Intermediate I undergoes further reactions, including protection and deprotection steps, to yield Intermediate II.

Final Coupling: Intermediate II is then coupled with a suitable glucosyl donor under basic conditions to form this compound

Industrial Production Methods: Industrial production of this compound typically involves large-scale synthesis using optimized reaction conditions to ensure high yield and purity. The process includes:

Refluxing: The reaction mixture is refluxed to facilitate the formation of the desired product.

Purification: The crude product is purified using techniques such as recrystallization and chromatography to obtain this compound with high purity

反応の種類： エンパグリフロジンは、以下を含むさまざまな化学反応を起こします。

酸化： エンパグリフロジンは、特定の条件下で酸化分解を起こし、分解生成物が形成される可能性があります.

加水分解： この化合物は、特に酸性および塩基性条件下で、加水分解を受けやすいです.

一般的な試薬と条件：

酸化分解： 過酸化水素などの試薬や他の酸化剤は、酸化分解を誘発する可能性があります。

加水分解： 塩酸や水酸化ナトリウムなどの酸性または塩基性条件は、加水分解を促進する可能性があります.

形成される主要な生成物：

酸化分解生成物： 使用される特定の条件と試薬に応じて、さまざまな酸化生成物が形成される可能性があります。

加水分解生成物： 加水分解は、より小さな断片と分解生成物の形成につながる可能性があります.

4. 科学研究への応用

エンパグリフロジンは、以下を含む幅広い科学研究への応用を持っています。

糖尿病の管理： エンパグリフロジンは、主に血糖値を下げることで2型糖尿病の管理に使用されます

心血管の利点： 研究によると、エンパグリフロジンは、2型糖尿病の患者における心筋梗塞や脳卒中などの心血管イベントのリスクを軽減できることが示されています

腎臓保護： エンパグリフロジンは、腎臓保護効果があり、腎臓病の進行リスクを軽減することが判明しています.

心不全： この化合物は、心不全の治療にも使用され、血糖値の管理を超えた利点を提供します.

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

エンパグリフロジンは、腎臓におけるナトリウム-グルコース共輸送体2（SGLT2）を阻害することで効果を発揮します。この阻害は、糸球体濾過液からのグルコースの再吸収を減らし、尿中へのグルコース排泄を増加させます。血糖値の低下は、2型糖尿病の管理に役立ちます。 さらに、エンパグリフロジンは、酸化ストレスの軽減や内皮機能の改善などのメカニズムを介して、心臓保護および腎臓保護効果があることが示されています .

Empagliflozin is part of the SGLT2 inhibitor class, which includes canagliflozin , dapagliflozin , and ertugliflozin . Below is a detailed comparison based on pharmacological properties, clinical outcomes, and safety profiles:

Selectivity for SGLT2 vs. SGLT1

This compound exhibits the highest selectivity for SGLT2 over SGLT1 among its peers, reducing off-target gastrointestinal effects (e.g., osmotic diarrhea). Canagliflozin has the lowest selectivity, which may contribute to its higher incidence of adverse events (AEs) .

Cardiovascular and Renal Outcomes

• Heart Failure Risk Reduction :
  this compound showed superior HHF risk reduction compared to DPP-4 inhibitors (HR 0.56; 95% CI 0.43–0.73) in the EMPRISE study . In contrast, canagliflozin demonstrated a 33% risk reduction in the CANVAS Program, but with a higher overall AE rate .

Adverse Event Profiles

This compound had the lowest AE rate per 100,000 prescriptions (44.07) compared to canagliflozin (82) and dapagliflozin (78) (p < 0.05) .

Metabolic Effects

• Weight Loss: this compound reduced body weight by 2.5–3.0 kg over 24 weeks, comparable to dapagliflozin but more pronounced than canagliflozin in head-to-head studies .
• Blood Pressure : Systolic blood pressure decreased by 3–5 mmHg with this compound, similar to other SGLT2 inhibitors .

Special Populations

• Renal Impairment : this compound maintains efficacy in mild-to-moderate renal impairment, whereas canagliflozin requires dose adjustments .
• Cardiovascular Safety : this compound is the only SGLT2 inhibitor with a proven mortality benefit in post-myocardial infarction patients, though recent trials like EMPACT-MI showed neutral effects on HHF risk .

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: