Enalaprilat

Title: Enalaprilat
CAS Registry Number: 76420-72-9
CAS Name: N-[(1S)-1-Carboxy-3-phenylpropyl]-L-alanyl-L-proline dihydrate
Additional Names: enalaprilic acid
Manufacturers' Codes: MK-422
Trademarks: Vasotec IV (Merck & Co.)
Molecular Formula: C18H24N2O5.2H2O
Molecular Weight: 384.42
Percent Composition: C 56.24%, H 7.34%, N 7.29%, O 29.13%
Literature References: Nonsulfhydryl dipeptide angiotensin converting enzyme (ACE) inhibitor. Prepn: A. A. Patchett et al., Nature 288, 280 (1980); eidem, EP 12401; E. E. Harris et al., US 4374829 (1980, 1983 both to Merck & Co.). Active metabolite of enalapril, q.v.: D. J. Tocco et al., Drug Metab. Dispos. 10, 15 (1982). Pharmacology: D. M. Gross et al., J. Pharmacol. Exp. Ther. 216, 552 (1981); M. A. Nelson et al., Clin. Exp. Pharmacol. Physiol. Suppl. 7, 87 (1982); T. A. Unger et al., Biochem. Pharmacol. 31, 3063 (1982). Bioavailability: M. L. Cohen et al., J. Pharmacol. Exp. Ther. 226, 192 (1983). Kinetics of enzyme inhibition: C. H. Reynolds, Biochem. Pharmacol. 33, 1273 (1984). Pharmacokinetics: K. S. Pang et al., Drug Metab. Dispos. 12, 309 (1984). Acute hemodynamic effects in essential hypertension: A. C. Simon et al., Clin. Pharm. Ther. 43, 49 (1988). Clinical evaluation in severe and malignant hypertension: D. J. DiPette et al., ibid. 38, 199 (1985).
Properties: Needles from H2O, mp 148-151°. [a]D -67.0° (0.1M HCl).
Melting point: mp 148-151°
Optical Rotation: [a]D -67.0° (0.1M HCl)
Therap-Cat: Antihypertensive.
Keywords: ACE-Inhibitor; Antihypertensive; N-Carboxyalkyl (peptide/lactam) Derivatives.
Enallylpropymal Enanthotoxin Encainide Enciprazine Endiandric Acids

Enalaprilat.svg
Systematic (IUPAC) name
(2S)-1-[(2S)-2-{[(1S)-1-carboxy-3-phenylpropyl]amino}propanoyl]pyrrolidine-2-carboxylic acid
Clinical data
AHFS/Drugs.com monograph
Licence data US FDA:link
Legal status  ?
Identifiers
CAS number 76420-72-9
ATC code  ?
ChemSpider 4575429
UNII GV0O7ES0R3 YesY
ChEBI CHEBI:4786
ChEMBL CHEMBL577
Chemical data
Formula C18H24N2O5 
Mol. mass 348.4 g/mol

Enalaprilat is the active metabolite of enalapril. It is the first dicarboxylate-containing ACE inhibitor and 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 esterification of enalaprilat with ethanol to produce enalapril.

As a prodrug, enalapril is metabolized 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. [1][2]