Preclinical Profile of Zofenopril: An Angiotensin Converting Enzyme Inhibitor with Peculiar Cardioprotective Properties

The discovery of captopril, the prototype of orally active angiotensin-converting enzyme inhibitors (ACEIs), represented a major breakthrough in the treatment of cardiovascular diseases. Currently, captopril has four important indications: hypertension, congestive heart failure, acute myocardial infarction, and diabetic nephropathy. After the discovery of captopril, several new ACEIs were developed and introduced into medical practice. These new ACEIs are neither chemically nor pharmacologically identical; they differ in their chemical structure, functional groups (sulfhydryl in captopril, carboxyl in enalapril, or phosphinyl in fosinopril), active moiety (some are prodrugs), potency, ancillary pharmacology, and pharmacokinetics. These and other important characteristics differentiate ACEIs and influence their ability to inhibit the enzyme in various organs. Since ACEIs appear to work by inhibiting angiotensin-converting enzyme (ACE) in critical tissues, tissue selectivity is one of the most important properties that varies with the individual ACEIs. An important question is whether different tissue-selectivity profiles of ACEIs in animal experiments are clinically relevant. Although the clinical relevance is not yet firmly established, the emerging evidence indicates that some differences among ACEIs are clinically significant (4,6,28,43). The latest ACE inhibitor to reach the European market is zofenopril calcium. By February 1999, it was registered in all 15 European Community countries. The goal of this review is to summarize all available preclinical data on zofenopril with a particular emphasis on its physicochemical properties and pharmacodynamic/pharmacokinetic characteristics, including its high lipophilicity and selective cardiac ACE inhibition, as well as the free radical scavenging properties of its sulfhydryl group. These properties are re-