Angiotensin-Converting Enzyme Inhibitors: Accomplishments and Challenges

Abstract

Two different structural types were proposed in 1977 (1) as leads for the development of nonpeptidic angiotensin-converting enzyme (ACE) inhibitors: mercaptoalkanoyl amino acids and carboxyalkanoyl amino acids.The development of the first structural type led to the identification of captopril, the first orally active ACE inhibitor to reach clinical application in hypertension and congestive heart failure. Elaboration of the second structural type by Patchett and collaborators led to the development of a new class of potent ACE inhibitors; carboxyalkyl dipeptides, and to the identification of enalapril, the second orally active ACE inhibitor to reach clinical application. Detailed structure-activity investigations (2, 3) indicate that both types of inhibitors bind to the active site in similar manner. The electrostatic interaction through the proline carboxyl, hydrogen bonding through the amide carbonyl, and the hydrophobic and/or entropic contributions of the five member ring of proline and the α-methyl group of the acyl moiety, are common to both captopril and enalapril. The critical interactions with the zinc ion on the enzyme are established through a sulfhydryl group, in the case of captopril, and a carboxyl group, in the case of enalapril, but enalapril is involved in at least two more binding interactions, through the amino group and the phenylalkyl side chain, and this is probably the reason for its higher intrinsic activity. X-ray crystallograpic studies of enzyme-inhibitor complexes in thermolysin (4, 5), a metalloprotease somewhat related to ACE, have shown that the sulfhydryl and carboxyl residues of the inhibitors become ligands of the active-site Zn, as postulated by Ondetti et al. (1).

Key Words:

• Captopril
• Enalapril
• Fosenopril
• Zinc binding
• Substituted proline