Structural relationships of angiotensin converting-enzyme inhibitors to pharmacologic activity

Abstract

The angiotensin converting-enzyme inhibitors available so far are active-site directed inhibitors. They utilize all the critical binding interactions of the substrate and convert the catalytic interaction with the zinc atom into an effective binding interaction. Three chemical classes of angiotensin converting-enzyme inhibitors have been introduced into clinical use, the sulfhydryl-containing inhibitors such as captopril and its analogs and prodrugs, carboxyalkyldipeptides such as enalapril and its analogs, and phosphorus-containing inhibitors such as fosinopril and the phosphonate SQ 29,852. Within each of the three groups of inhibitors significant differences in molecular weight and polarities can be observed. These differences have a significant influence in the routes of elmination and tissue distribution of these inhibitors. Tissue distribution and intrinsic potency will determine the magnitude of angiotensin converting-enzyme inhibition at the tissue level, which could play a critical role in the clinical utilization of these inhibitors. The sulfhydryl-containing inhibitors such as captopril undergo a metabolic process significantly different from that of the other two classes. They can interact with endogenous sulfhydryl-containing compounds like glutathione and proteins, to form reversible disulfides, which can serve as depot forms of the drug. Also, because of their redox properties they might function as recyclable free radical scavengers.