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Enalapril

Systematic (IUPAC) name

(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylic acid

(Diagrams above are enalapril and enalaprilat, respectively. Data below refers to enalapril unless indicated)

Clinical data

Trade names

Vasotec

AHFS/Drugs.com

monograph

MedlinePlus

a686022

Pregnancy cat.

C,D

Chemical data

Formula

C20H28N2O5

Mol. mass

376.447 g/mol

InChI[show]

Enalapril 3D structure

Enalapril (marketed as Vasotec in the USA and Enaladex in some other countries) is an angiotensin converting enzyme (ACE) inhibitorused in the treatment of hypertension and some types of chronic heart failure. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like enalapril prevent this effect. Enalapril has been shown to lower the death rate in systolic heart failure.[1] Enalapril was the first member of the group of ACE inhibitors known as the dicarboxylatecontaining ACE inhibitors.
[edit]Enalaprilat

Enalaprilat, the first dicarboxylate-containing ACE inhibitor, was developed partly to overcome these limitations of captopril. The sulfhydryl-moiety was replaced by a carboxylate-moiety, but additional modifications were required in its structurebased design to achieve a similar potency to captopril. Enalaprilat, however, had a problem of its own. The consequence of the structural modifications was that it proved to have unfavourable ionisation characteristics to allow sufficient potency for oral administration (in tablets). Thus enalaprilat was only suitable for intravenousadministration. This was overcome by the researchers at Merck by the esterification of enalaprilat with ethanol to produce enalapril. As a prodrug, enalapril is metabolised in vivo to the active form enalaprilat by various esterases. Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites. The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects. Renal impairment [particularly creatinine clearance < 20 ml/min (< 1.2 L/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure.
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prototype for others

Most importantly, perhaps, the QSAR-based modifications in structure serendipitously led to an improved understanding of the structure of ACE which aided in the development of subsequent carboxylate-containing ACE inhibitors. Enalapril is a prodrug that is converted by deesterification to converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies.
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