Enalapril

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Enalapril
Enalapril-structural.svg
Enalapril VanDerVals transparent.png
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 namesVasotec
AHFS/Drugs.commonograph
MedlinePlusa686022
Pregnancy cat.C,D
Legal status Prescription only
RoutesI.V. and P.O.
Pharmacokinetic data
Bioavailability60% (oral)
Metabolismhepatic (to enalaprilat)
Half-life11 hours (enalaprilat)
Excretionrenal
Identifiers
CAS number75847-73-3 YesY
ATC codeC09AA02
PubChemCID 5388962
DrugBankDB00584
ChemSpider4534998 YesY
UNII69PN84IO1A YesY
KEGGD07892 YesY
ChEBICHEBI:4784 YesY
ChEMBLCHEMBL578 YesY
Chemical data
FormulaC20H28N2O5 
Mol. mass376.447 g/mol
 YesY (what is this?)  (verify)
 
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Enalapril
Enalapril-structural.svg
Enalapril VanDerVals transparent.png
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 namesVasotec
AHFS/Drugs.commonograph
MedlinePlusa686022
Pregnancy cat.C,D
Legal status Prescription only
RoutesI.V. and P.O.
Pharmacokinetic data
Bioavailability60% (oral)
Metabolismhepatic (to enalaprilat)
Half-life11 hours (enalaprilat)
Excretionrenal
Identifiers
CAS number75847-73-3 YesY
ATC codeC09AA02
PubChemCID 5388962
DrugBankDB00584
ChemSpider4534998 YesY
UNII69PN84IO1A YesY
KEGGD07892 YesY
ChEBICHEBI:4784 YesY
ChEMBLCHEMBL578 YesY
Chemical data
FormulaC20H28N2O5 
Mol. mass376.447 g/mol
 YesY (what is this?)  (verify)
Enalapril 3D structure

Enalapril (marketed as Vasotec in the USA, Enaladex in some other countries, and Enacard for veterinary use[1]) is an angiotensin converting enzyme (ACE) inhibitor used in the treatment of hypertension, diabetic nephropathy, and some types of chronic heart failure. ACE converts the peptide hormone angiotensin I to angiotensin II. One of the actions of angiotensin II is the vasoconstriction of blood vessels resulting in an increase in blood pressure. ACE inhibitors such as enalapril prevent this effect. Enalapril has been shown to lower the death rate in systolic heart failure.[2] Enalapril was the first member of the group known as the dicarboxylate-containing ACE inhibitors.

Development[edit]

Enalapril as a treatment for high blood pressure works by modulating the renin-angiotensin-aldosterone system (RAAS).

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 prodrug.

Enalaprilat[edit]

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 it proved to have unfavourable ionisation characteristics to allow sufficient potency for oral administration (in tablets). Thus, it 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 two to four hours after oral administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life two to six 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[edit]

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, a prodrug, is converted by de-esterification 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[edit]

Most common side effects include hypotension, dizziness when standing up, and dry cough.[3]

Synthesis[edit]

Enalapril reductive amination.png[4]

References[edit]

  1. ^ Enacard listed at http://www.drugs.com.
  2. ^ McMurray JJV, Systolic heart failure, N Engl J Med, 362:228, Jan. 21, 2010).
  3. ^ Listed at http://www.drugs.com.
  4. ^ Patchett, A. A.; in Chronicles of Drug Discovery, Vol. 3; Lednicer, D., ed., ACS Books, Washington, DC, 1993, 125.

External links[edit]