Design of new antihypertensive drugs: Potent and specific inhibitors of angiotensin-converting enzyme

Abstract

The similarity of the biologically important enzyme angiotensin-converting enzyme to the structurally characterized digestive enzyme carboxypeptidase A has led us to develop a hypothetical model of the mechanism of binding of substrates to its active site. In this model, a positively charged group on the enzyme forms an ionic bond with the negatively charged carboxyl group of the substrate; a hydrogen bonding group of the enzyme binds with the terminal peptide bond of the substrate, and the tightly bound zinc ion of the enzyme binds to the penultimate (scissile) peptide bond of the substrate. Succinyl- l-proline (SQ 13,745) was synthesized as a potential inhibitor of angiotensin-converting enzyme by analogy to d-2-benzylsuccinic acid, an inhibitor of carboxypeptidase A; it was a moderately potent but specific inhibitor of the enzyme. Structure-activity studies carried out using the hypothetical model as a guide led to the synthesis of d-2-methyl-succinyl- l-proline (SQ 13,-297) and d-2-methylglutaryl- l-proline (SQ 14,-102), more potent inhibitors of the enzyme that were shown to be orally active in rats. Attempts to replace the zinc-binding carboxyl group of these compounds with groups with greater affinity for zinc have led to the synthesis of extremely potent inhibitors such as 3-mercapto-propanoyl- l-proline (SQ 13,863) and d-3-mercapto-2-methylpropanoyl- l-proline (SQ 14,225). The most active compound, SQ 14,225, is a purely competitive inhibitor of angiotensin-converting enzyme with an enzyme-inhibitor dissociation constant ( K i) of 1.7 × 10 −9 M. It is an extremely potent and specific inhibitor of angiotensin-converting enzyme and appears to have great potential for the treatment of hypertensive disease.