Article: 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. weight	376.447 g/mol
Pharmacokinetic data
Bioavailability	60% (oral)
Metabolism	hepatic (to enalaprilat)
Half life	11 hours (enalaprilat)
Excretion	renal
Therapeutic considerations
Pregnancy cat.	D (Australia)
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®.

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-moeity of captoril 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-moeity was replaced by a carboxylate-moeity, 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.

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.