Enalaprilat

Enalaprilat

Systematic (IUPAC) name
(2S)-1-[(2S)-2-{[(1S)-1-carboxy-3-phenylpropyl]amino}propanoyl]pyrrolidine-2-carboxylic acid
Clinical data
AHFS/Drugs.com	monograph
License data	US FDA: Enalaprilat
Identifiers
CAS Number	76420-72-9
IUPHAR/BPS	6332
ChemSpider	4575429
UNII	GV0O7ES0R3
ChEBI	CHEBI:4786
ChEMBL	CHEMBL577
Chemical data
Formula	C18H24N2O5
Molar mass	348.4 g/mol
SMILES C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N2CCC[C@H]2C(=O)O
InChI InChI=1S/C18H24N2O5/c1-12(16(21)20-11-5-8-15(20)18(24)25)19-14(17(22)23)10-9-13-6-3-2-4-7-13/h2-4,6-7,12,14-15,19H,5,8-11H2,1H3,(H,22,23)(H,24,25)/t12-,14-,15-/m0/s1 Key:LZFZMUMEGBBDTC-QEJZJMRPSA-N

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 potency similar to captopril.

Enalaprilat, however, had a problem of its own. The consequence of the structural modifications was to give it ionisation characteristics that do not allow sufficient GI absorption 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]

References

1. D. J. Tocco; et al. (1982). "The physiological disposition and metabolism of enalapril maleate in laboratory animals". Drug Metab Dispos. 10 (15): 15–19.
2. A. C. Simon; et al. (1988). "Acute Hemodynamic Effects in Essential Hypertension". Clin. Pharm. Ther. 43 (49).