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Enalapril



Enalapril
Systematic (IUPAC) name
1-[2-(1-ethoxycarbonyl-3-phenyl-propyl) aminopropanoyl] pyrrolidine-2-carboxylic acid.

(Diagrams above are enalpril and enalaprilat, respectively. Data below refers to enalapril unless indicated)
Identifiers
CAS number 75847-73-3
ATC code C09AA02
PubChem 5362032
DrugBank APRD00510
Chemical data
Formula C20H28N2O5 
Mol. mass 376.447 g/mol
Pharmacokinetic data
Bioavailability 60% (oral)
Metabolism hepatic (to enalaprilat)
Half life 11 hours (enalaprilat)
Excretion renal
Therapeutic considerations
Pregnancy cat.

?(AU)

Legal status

Prescription only

Routes  ?

Enalapril is an angiotensin converting enzyme (ACE) inhibitor used in the treatment of hypertension and some types of chronic heart failure. Enalapril was the first member of the group of ACE inhibitors known as the dicarboxylate-containing ACE inhibitors. It is marketed by Merck & Co. (Merck, Sharp & Dohme) under the trade names, Renitec® and Vasotec®. The primary effect of enalapril, as with all ACE inhibitors, is to lower blood pressure.

Additional recommended knowledge

Development

Enalapril was developed by researchers at Merck & Co. as part of their efforts to develop novel treatments for hypertension by modulating the renin-angiotensin-aldosterone (RAS) system.

The success of Squibb in developing the first inhibitor, captopril, provided a major impetus for Merck's research laboratories to develop a competing product. Captopril was not without its problems, however, as it was believed (and shown to be true) that the sulfhydryl-moiety of captopril was responsible for such adverse effects as metallic taste.

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 itself, however, was not without its problems. The consequence of the structural modifications was that it proved to be 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.

 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Enalapril". A list of authors is available in Wikipedia.
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