Enalapril

Synthetic Routes and Reaction Conditions: Enalapril is synthesized through a multi-step process. The synthesis begins with the preparation of the key intermediate, L-alanyl-L-proline. This intermediate is then coupled with a phenylbutyric acid derivative to form this compound. The reaction conditions typically involve the use of organic solvents and catalysts to facilitate the coupling reaction.

Industrial Production Methods: In industrial settings, this compound is produced by reacting L-alanyl-L-proline with a phenylbutyric acid derivative under controlled conditions. The reaction mixture is then purified through crystallization and filtration to obtain the final product. The industrial process ensures high yield and purity of this compound, making it suitable for pharmaceutical use .

Types of Reactions: Enalapril undergoes several types of chemical reactions, including hydrolysis, oxidation, and substitution.

Common Reagents and Conditions:

Hydrolysis: this compound is hydrolyzed in the liver to form its active metabolite, enalaprilat. This reaction is catalyzed by liver enzymes.

Oxidation: this compound can undergo oxidation reactions in the presence of oxidizing agents, leading to the formation of various oxidation products.

Substitution: this compound can participate in substitution reactions with nucleophiles, resulting in the formation of substituted derivatives.

Major Products Formed: The major product formed from the hydrolysis of this compound is enalaprilat, which is the active form of the drug. Oxidation and substitution reactions can lead to the formation of various by-products, depending on the reagents and conditions used .

Indications

Enalapril is primarily indicated for:

• Hypertension : Effective in lowering blood pressure across various forms of hypertension, including essential and renovascular hypertension.
• Heart Failure : Improves symptoms and functional capacity in patients with heart failure, particularly those with reduced ejection fraction.
• Asymptomatic Left Ventricular Dysfunction : Helps prevent progression to symptomatic heart failure.

Hypertension Management

This compound effectively lowers blood pressure without causing reflex tachycardia. Studies have shown that it maintains antihypertensive effects for at least 24 hours after administration. Long-term use leads to further reductions in blood pressure and improved patient outcomes .

Heart Failure Treatment

This compound has demonstrated significant benefits in patients with heart failure:

• Symptom Improvement : Clinical trials indicate improved exercise tolerance and reduced breathlessness .
• Echocardiographic Enhancements : Reductions in left ventricular dimensions and improvements in systolic time intervals have been observed .
• Long-term Benefits : Patients on this compound show increased exercise capacity over extended treatment periods .

Cardiovascular Risk Reduction

Research indicates that this compound may reduce arterial stiffness, which is particularly beneficial for populations at risk for cardiovascular diseases, such as those with rheumatoid arthritis .

Case Study 1: Heart Failure Improvement

In a double-blind study involving 20 patients with heart failure, this compound treatment led to significant improvements in functional class and exercise performance over eight weeks. Plasma concentrations of harmful hormones decreased while beneficial potassium levels increased .

Case Study 2: Hypertension Control

A randomized controlled trial showed that patients receiving this compound experienced a significant drop in systolic blood pressure compared to those on placebo. The study highlighted the drug's efficacy even in patients with low-renin hypertension .

Data Tables

Enalapril exerts its effects by inhibiting the angiotensin-converting enzyme, which is responsible for converting angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor that increases blood pressure by narrowing blood vessels. By inhibiting this enzyme, this compound reduces the production of angiotensin II, leading to the relaxation of blood vessels and a decrease in blood pressure. The molecular targets of this compound include the angiotensin-converting enzyme and the renin-angiotensin-aldosterone system, which plays a crucial role in blood pressure regulation and fluid balance .

Structural and Functional Analogues of Enalapril

ACE Inhibitors

This compound shares structural and functional similarities with other ACE inhibitors, as identified by computational tools like SuperPred (Tanimoto coefficient >0.8). Key analogues include spirapril, imidapril, lisinopril, ramipril, and trandolapril .

Table 1: Comparative Efficacy of ACE Inhibitors

Angiotensin Receptor–Neprilysin Inhibitors (ARNI)

Sacubitril/Valsartan (ARNI) represents a newer class of drugs combining neprilysin inhibition with angiotensin receptor blockade.

Table 2: Sacubitril/Valsartan vs. This compound in Heart Failure

Angiotensin Receptor Blockers (ARBs)

ARBs like olmesartan and losartan target angiotensin II receptors directly, offering an alternative to ACE inhibitors.

Table 3: ARBs vs. This compound

Combination Therapies

This compound is often combined with other agents to enhance efficacy or reduce side effects.

Table 4: this compound-Based Combinations

Specialized Comparisons

Side Effect Profiles

• Cough Incidence : Imidapril (0.9%) vs. This compound (7.0%) in hypertensive patients .
• Hyperkalemia Risk : Similar rates between this compound and olmesartan in CKD patients .

Mechanistic Differences in Organ Protection

• Cardiac Remodeling : this compound outperformed hydralazine in reducing cardiomyocyte hypertrophy and fibrosis in CKD mice .
• Diabetic Nephropathy : this compound and bosentan similarly reduced TGF-β1 and PAI-1 in diabetic rats, but only this compound inhibited ERK signaling .

Enalapril is an angiotensin-converting enzyme (ACE) inhibitor widely used in the treatment of hypertension and heart failure. This article delves into its biological activity, mechanisms of action, clinical efficacy, and research findings.

This compound is a prodrug that is converted in the liver to its active form, enalaprilat. This conversion is crucial for its pharmacological effects. The primary mechanism involves the inhibition of ACE, leading to decreased production of angiotensin II, a potent vasoconstrictor. This results in:

• Decreased blood pressure : By reducing vascular resistance.
• Increased plasma renin activity : Due to the loss of feedback inhibition from angiotensin II.
• Reduced aldosterone secretion : Although long-term use may normalize aldosterone levels .

Additionally, this compound may influence bradykinin levels, which can contribute to its vasodilatory effects, although this mechanism is not fully understood .

Hypertension

This compound has demonstrated significant efficacy in lowering blood pressure across various populations. A multicenter trial involving 265 patients with essential hypertension showed that monotherapy with this compound resulted in normotension in 73% of younger patients and about 50% of middle-aged patients after eight weeks .

Heart Failure

In patients with chronic heart failure, this compound has been associated with improvements in symptoms and exercise capacity. A study involving 36 patients on stable digoxin and diuretic therapy found significant improvements in functional class and exercise duration after three months of this compound treatment compared to placebo .

Case Studies

• Effects on Arterial Stiffness :
  A randomized controlled trial assessed the impact of this compound on arterial stiffness in women with rheumatoid arthritis. After 12 weeks, the group receiving this compound showed a trend towards reduced Cardio-Ankle Vascular Index (CAVI), suggesting potential cardiovascular benefits beyond blood pressure reduction .
• Inflammation and Cardiovascular Risk :
  Chronic treatment with this compound has been shown to attenuate levels of pro-inflammatory cytokines, indicating a possible role in reducing cardiovascular risk factors associated with inflammation .

Summary of Clinical Studies

Q. Basic: What are the key considerations when designing a randomized controlled trial (RCT) to evaluate enalapril's efficacy in heart failure?

Answer:
Critical design elements include:

• Double-blind, placebo-controlled protocols to minimize bias, as seen in the PARADIGM-HF trial comparing LCZ696 (sacubitril/valsartan) with this compound .
• Primary endpoints such as composite outcomes (e.g., cardiovascular death or hospitalization for heart failure) and secondary endpoints (e.g., symptom improvement, renal function) .
• Sample size calculation powered to detect clinically meaningful differences (e.g., 8442 patients in PARADIGM-HF) and stratification by baseline characteristics (e.g., ejection fraction, NYHA class) .
• Statistical methods : Cox proportional hazards models for time-to-event analysis, intention-to-treat principles, and sensitivity analyses for missing data .

Q. Advanced: How can network pharmacology and molecular docking elucidate this compound's off-target effects in non-cardiovascular conditions?

Answer:

• Network pharmacology identifies overlapping targets between this compound and disease pathways (e.g., rheumatoid arthritis via TNF, CASP3, MMP9) by integrating drug-target databases (e.g., SwissTargetPrediction) and disease gene sets (e.g., DisGeNET) .
• Molecular docking predicts binding affinities (e.g., this compound’s H-bond interactions with TNF’s Lys89, CASP3’s Arg207) using software like AutoDock. Validation requires in vitro assays (e.g., enzyme inhibition) and in vivo models (e.g., collagen-induced arthritis) .
• Statistical validation : Use RMSD values (<2 Å) and binding scores (e.g., -8.2 kcal/mol for MMP9) to prioritize targets for experimental validation .

Q. Basic: What statistical approaches are appropriate for analyzing this compound's effect on cardiovascular mortality in large-scale trials?

Answer:

• Cox regression models to calculate hazard ratios (HR) and 95% confidence intervals (CI), as used in the SOLVD trial (HR 0.84 for all-cause mortality) .
• Prespecified subgroup analyses to assess consistency across demographics (e.g., age, race) .
• Handling covariates : Adjust for baseline blood pressure, renal function, and concomitant medications to isolate this compound’s effects .
• Sensitivity analyses to address competing risks (e.g., non-cardiovascular deaths) .

Q. Advanced: How do conflicting findings on this compound's renoprotective effects in diabetic patients inform future research?

Answer:

• Contradictory evidence : this compound did not slow nephropathy progression in type 1 diabetes (mesangial volume unchanged) but showed non-inferiority to telmisartan (an ARB) in type 2 diabetic nephropathy .
• Hypotheses : Differences may arise from disease stage (normoalbuminuria vs. overt nephropathy), diabetic subtypes, or genetic factors (e.g., ACE polymorphisms).
• Methodological recommendations : Prioritize renal biopsy endpoints (e.g., glomerular filtration rate) over surrogate markers (e.g., albuminuria) and extend follow-up beyond 5 years .

Q. Basic: What experimental models are used to assess this compound's impact on endothelial dysfunction?

Answer:

• Ex vivo vascular ring assays : Measure acetylcholine-induced relaxation in aortic rings pre-treated with this compound. Use inhibitors (e.g., DETCA for superoxide dismutase) to isolate oxidative stress pathways .
• Outcome metrics : Percent relaxation relative to baseline, analyzed via one-way ANOVA and post-hoc tests (e.g., Dunnett’s) .
• Validation : Correlate findings with in vivo biomarkers (e.g., plasma nitric oxide levels) .

Q. Advanced: What mechanisms underlie racial disparities in this compound's therapeutic response among heart failure patients?

Answer:

• Pharmacogenomic factors : Polymorphisms in ACE (e.g., I/D alleles) or angiotensinogen genes may alter drug metabolism or RAAS activation .
• Clinical evidence : In the SOLVD trial, this compound reduced heart failure hospitalizations in white patients (HR 0.56) but not Black patients, independent of blood pressure changes .
• Research implications : Incorporate genetic profiling (e.g., genome-wide association studies) and pharmacokinetic analyses in diverse cohorts to optimize dosing .

Q. Basic: How is echocardiography utilized to evaluate this compound's effect on left ventricular (LV) remodeling?

Answer:

• Key parameters : LV end-diastolic/systolic volumes, ejection fraction, and mass, measured via blinded core lab analysis .
• Protocols : Standardized imaging at baseline, 4 months, and 12 months to track progression (e.g., SOLVD substudy) .
• Statistical analysis : Linear mixed models to compare this compound vs. placebo effects on LV structural changes .

Q. Advanced: What methodological challenges arise when combining this compound with nutraceuticals like folic acid in stroke prevention trials?

Answer:

• Stratification by genetic factors : The CSPPT trial stratified patients by MTHFR C677T genotype to account for folate metabolism variability .
• Endpoint selection : Composite outcomes (e.g., first stroke) require large cohorts (e.g., 20,702 participants) and long follow-up (median 4.5 years) .
• Synergy assessment : Use factorial designs to distinguish additive vs. synergistic effects and adjust for confounding factors (e.g., dietary folate intake) .