Stereochemistry-activity relationships of ACE inhibitors. Conformational studies by1H and13C NMR of perindopril and selected stereoisomers

Abstract

Perindopril, the tert-butylamine salt of 1-{(2S)-2-[(1S)-(1-carbethoxybutyl)amino]-1-oxopropyl}-(2S,3aS,7aS)-perhydroindole-2-carboxylic acid, is an inhibitor of angiotensin-converting enzyme (ACE) and a new drug for the treatment of hypertension. The interaction between the inhibitor and the enzyme was investigated by studying the active diacid metabolite of perindopril, its stereoisomers and a desmethyl analogue. The pharmacological study allowed the measurement of the in vitro activities of the different compounds. The 1H and 13C NMR studies have shown that the cis-trans equilibrium about the amide bond is strongly dependent on the configuration of the chiral centres and on the pH of the solution. The pKa of the different acid-base species were measured. The results show that perhydroindole derivatives are potent inhibitors of ACE as long as they fulfil the following basic requirements: (1) an S configuration of the carbon bearing the terminal carboxy group; (2) an S methyl substituent in the alanine residue; however, the inhibitor potency is not modified on the replacement of the alanine residue of the perindopril by a glycine residue; and (3) less stringently, an S configuration of the C-1 butyl carbon. Under these conditions the Zn binding ligand (chain carboxylate group) is devoid of steric hindrance in the trans conformers. No direct relationship appeared between the relative amount of the trans form and the activity. The cyclic skeleton of the perhydroindole derivatives provided a strong hydrophobic interaction with the active enzymatic site, whatever the configurations at C-3a and C-7a. Lipophilic interactions involving the different parts of the inhibitor are not independent of each other.