N-(1-carboxy-3-phenylpropyl)phenylalanyl-alpha-asparagine

Summary

Enalapril diacid is the active diacid form of the ACE‑inhibitor enalapril. It belongs to the RAAS‑acting peptide family and is prescribed to lower elevated blood pressure by blocking the conversion of angiotensin I to the vasoconstrictor angiotensin II. The compound can be given intravenously or taken orally.

Mechanism of Action

Enalapril diacid binds tightly to the active site of angiotensin‑converting enzyme (ACE), preventing the cleavage of angiotensin I into angiotensin II and the breakdown of bradykinin. Kinetic studies show a Ki of ~0.06 nM and a slow dissociation half‑time of about 60 min, giving prolonged enzyme inhibition. The resulting reduction in angiotensin II levels leads to vasodilation, decreased peripheral resistance, and lower arterial pressure.

What the Research Shows

In vitro, enalapril diacid inhibited rabbit lung ACE with an IC50 of 0.51 nM. In conscious dogs, intravenous doses (10–300 µg kg⁻¹) produced dose‑related plasma ACE inhibition and blunted angiotensin I pressor responses without altering basal blood pressure. Anesthetized dogs showed increased cardiac output and reduced total peripheral resistance, indicating vasodilatation. Oral administration to spontaneously hypertensive rats lowered systolic pressure over a wide dose range (3 × 10⁻⁷–10⁻⁵ mol kg⁻¹) with long duration of action. Chronic oral dosing (0.5 mg kg⁻¹ daily) sustained 24‑hour blood‑pressure control. Regional studies in dogs revealed selective renal vasodilation, especially in the inner cortex, and modest effects on coronary flow. Kinetic work demonstrated a slow onset and prolonged dissociation from ACE, supporting the long‑acting profile. In humans with renal impairment, oral enalapril (5 mg) produced markedly increased plasma diacid concentrations and AUC, prolonging ACE inhibition, while urinary excretion remained high.

Reported Benefits

Animal data show that enalapril diacid is a highly potent and long‑acting ACE inhibitor, effective at low oral doses and capable of sustained 24‑hour blood‑pressure reduction. It improves renal blood flow, particularly in the inner cortex, and produces vasodilation without major changes in heart rate. Pharmacokinetic studies indicate that it remains active after oral dosing, and its prolonged enzyme inhibition may be advantageous for hypertension management, especially when renal function is moderately impaired.

Limitations of the Evidence

The majority of efficacy evidence comes from rabbit, dog, and rat studies; direct clinical outcome data in humans are not presented in the cited abstracts. In severe renal impairment, plasma concentrations rise dramatically, raising the risk of excess ACE inhibition. The long dissociation from ACE may also prolong hypotensive effects, requiring careful dosing. Comparative data with other ACE inhibitors are limited to animal potency measures.

Safety Considerations

No adverse events were reported in the animal studies, though mild increases in cardiac rate and contractility were observed in dogs. Human pharmacokinetic work shows that severe renal dysfunction markedly elevates plasma enalapril diacid levels, suggesting a need for dose adjustment. Caution is advised in patients with advanced kidney disease, and monitoring for hypotension or electrolyte disturbances is prudent.

How It Is Administered

Enalapril diacid is formulated for both intravenous injection and oral tablets. Intravenous dosing in dogs ranged from 10 to 300 µg kg⁻¹, while oral antihypertensive effects were demonstrated in rats at doses as low as 0.13 mg kg⁻¹. In humans, a single oral dose of 5 mg yields measurable plasma diacid concentrations.

Routes of Administration

Goals & Uses

• Hypertension managementCardiovascularHigh
• Heart failure treatmentCardiovascularHigh
• Post-myocardial infarction cardioprotectionCardiovascularHigh
• Left ventricular dysfunctionCardiovascularHigh
• Diabetic nephropathy / renoprotectionRenalModerate

Contraindications

• Hereditary or idiopathic angioedemaImmunologic/AllergicHigh
• Pregnancy (2nd and 3rd trimester)ObstetricHigh
• Hypersensitivity to enalapril or any componentAllergicHigh
• Concomitant use with aliskiren in diabetesDrug InteractionHigh
• History of ACE inhibitor-induced angioedemaImmunologic/AllergicHigh

Adverse Effects

• Renal impairment/acute kidney injuryRenalUncommon
• Hypotension (first-dose)CardiovascularCommon
• Elevated serum creatinine/BUNRenalCommon
• HyperkalemiaElectrolyte ImbalanceCommon
• Dry coughRespiratoryCommon
• AngioedemaImmunologicRare

Drug Interactions

• NSAIDs (e.g., ibuprofen, indomethacin)Moderate
• Potassium-sparing diuretics (e.g., spironolactone, amiloride)High
• AliskirenHigh
• Antidiabetic agents (insulin, sulfonylureas)Low
• LithiumModerate

Population Constraints

• PregnancyReproductive SafetyAbsolute
• Pediatric patients (neonates/premature infants)PediatricRelative
• Black patientsEthnicity/PharmacogenomicsRelative
• Severe renal impairment (eGFR <30 mL/min)RenalRelative
• Bilateral renal artery stenosisVascularRelative

Regulatory Status

• European UnionApprovedApproved: Hypertension, Heart failure, Prevention of symptomatic heart failure in patients with asymptomatic LV dysfunctionEnalapril and enalaprilat approved via EMA; multiple national authorizations across EU member states.
• United StatesApprovedApproved: Hypertension (IV for when oral therapy is not practical), Heart failure, Asymptomatic left ventricular dysfunctionEnalaprilat IV (Vasotec IV) approved by FDA. Enalapril maleate oral approved separately. Active diacid form is the IV drug.
• United KingdomApprovedApproved: Hypertension, Heart failure, Prevention of symptomatic heart failureApproved by MHRA; oral enalapril widely available; IV enalaprilat available for hospital use.

Enalaprilat (the active diacid) is FDA-approved as an intravenous formulation (Vasotec IV). Enalapril maleate (prodrug) is widely approved orally across US, EU, and UK. The active diacid form itself is marketed for IV use.

Evidence & Sources

• Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin-converting enzyme
  Journal ArticleLowCarr RD, et al.1990-01-01T00:00:00.000000Z
• Kinetics of inhibition of angiotensin converting enzyme by captopril and by enalapril diacid
  Journal ArticleLowReynolds CH1984-01-01T00:00:00.000000Z
• Regional vasodilating effects of spirapril diacid and enalapril diacid in anesthetized dogs
  Journal ArticleLowNoguchi K, et al.1991-01-01T00:00:00.000000Z
• Simultaneous measurement of renal blood flow of the outer and inner cortex by laser-Doppler flowmetry in anesthetized dogs: effect of enalapril diacid
  Journal ArticleLowNoguchi K, et al.1992-01-01T00:00:00.000000Z
• [Ex vivo and in vitro effects of trandolapril on the efflux of 22Na from the caudal artery of the SHR rat. Inhibition of vascular angiotensin II production]
  Journal ArticleLowMoura AM, Worcel M1988-01-01T00:00:00.000000Z
• Pharmacokinetics of temocapril and enalapril in patients with various degrees of renal insufficiency
  Journal ArticleLowOguchi H, et al.1993-01-01T00:00:00.000000Z

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