Enalaprilat

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 thiol functional group of captopril was replaced with a carboxylic acid group, but additional modifications were required to achieve a potency similar to captopril.

Enalaprilat

Clinical data
AHFS/Drugs.com	Monograph
License data	US FDA: Enalaprilat
Identifiers
IUPAC name (2S)-1-[(2S)-2-{[(1S)-1-carboxy-3-phenylpropyl]amino}propanoyl]pyrrolidine-2-carboxylic acid
CAS Number	84680-54-6 anhydrous: 76420-72-9
IUPHAR/BPS	6332
ChemSpider	4575429
UNII	GV0O7ES0R3 anhydrous: Q508Q118JM
ChEBI	CHEBI:4786
ChEMBL	ChEMBL577
CompTox Dashboard (EPA)	DTXSID0048975
ECHA InfoCard	100.071.306
Chemical and physical data
Formula	C18H24N2O5
Molar mass	348.399 g·mol^−1
3D model (JSmol)	Interactive image
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, however, had a problem of its own. The consequence of the structural modifications was that its ionisation characteristics do not allow for sufficient GI absorption. Thus, enalaprilat was only suitable for intravenous administration. This was overcome by the monoesterification of enalaprilat with ethanol to produce enalapril.

As a prodrug, enalapril is hydrolyzed 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. Tocco DJ, deLuna FA, Duncan AE, Vassil TC, Ulm EH (1982). "The physiological disposition and metabolism of enalapril maleate in laboratory animals". Drug Metabolism and Disposition. 10 (1): 15–9. PMID 6124377.
2. Simon AC, Chau NP, Levenson J (January 1988). "Brachial artery hemodynamic response to acute converting enzyme inhibition by enalaprilat in essential hypertension". Clinical Pharmacology and Therapeutics. 43 (1): 49–54. doi:10.1038/clpt.1988.10. PMID 2826067. S2CID 33083327.