Angiotensin-Converting Enzyme Inhibitors : Synthesis and Structure-Activity Relationships of Potent N-Benzyloxycarbonyl Tripeptide Inhibitors

Abstract

A new series of γ-D-Glu-containing N-benzyloxycarbonyl (Z) tripeptide inhibitors of angiotensin-converting enzyme (ACE) was synthesized. The effect of varying the antepenultimate amino acid residue in this series on the biological activity was studied. Introduction of Lys and Orn residues at the P₁ position provided the most potent inhibitors, 25a and 25b (IC₅₀ : 3.5 and 4.9×10^-9M, respectively), which exhibited an oral antihypertensive activity. This result suggests that basic amino acid residues at the P₁ position play an important role in binding with the S₁ subsite of ACE in this series. Oral antihypertensive activity of selected compounds was evaluated.