Angiotensin-converting enzyme inhibitors: importance of the amide carbonyl of mercaptoacyl amino acids for hydrogen bonding to the enzyme

Abstract

A series of mercaptoacyl amino acids and related compounds was synthesized and evaluated for inhibition of angiotensin-converting enzyme (ACE) to determine the nature and importance of the putative interaction between ACE and the amide moiety of inhibitors such as captopril (3-mercapto-2-methylpropanoyl-L-proline). Evidently, the interaction involves a H-bond from a donor site on ACE to the O of the amide carbonyl. Compounds in which the amide moiety is replaced by other groups (ester, ketone, sulfonamide) capable of accepting a H-bond are effective inhibitors, but compounds in which only the geometrical features of the amide are retained are ineffective inhibitors. The presence of an NH group is not necessary for effective inhibition. The activity of a series of mercaptoacyl cycloalkyl carboxylic acids parallels the activity of the isosteric series of mercaptoacyl imino acids.