Enalapril

Not to be confused with Allopurinol.

Enalapril

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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
Pregnancy category	C,D
Routes of administration	I.V. and P.O.
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	60% (oral)
Metabolism	hepatic (to enalaprilat)
Biological half-life	11 hours (enalaprilat)
Excretion	renal
Identifiers
CAS Number	75847-73-3
ATC code	C09AA02 (WHO)
PubChem	CID 5388962
DrugBank	APRD00510
ChemSpider	4534998
Chemical data
Formula	C20H28N2O5
Molar mass	376.447 g/mol[[]]
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File:Enalapril 3D animation.gif

Enalapril 3D structure

Enalapril (marketed as Renitec and Vasotec) is an angiotensin converting enzyme (ACE) inhibitor used 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. Enalapril was the first member of the group of ACE inhibitors known as the dicarboxylate-containing ACE inhibitors.

Development

Enalapril is a treatment for high blood pressure that works by modulating the renin-angiotensin-aldosterone (RAS) system.

Squibb developed the first inhibitor, captopril, but it had adverse effects such as a metallic taste (which, as it turned out, was due to the sulfhydryl group). Merck & Co. developed enalapril as a competing product.

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 structure-based 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 intravenous administration. 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.

A 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.

Side Effects

Most common side effects include hypotension, dizziness when standing up, and dry cough.

Synthesis

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Patchett, A. A.; in Chronicles of Drug Discovery, Vol. 3; Lednicer, D., ed., ACS Books, Washington, DC, 1993, 125.

External links

• Prescribing Information for VASOTEC

ar:إنالابريل uk:Еналаприл