Synthesis and biological activity of a ketomethylene analog of a tripeptide inhibitor of angiotensin converting enzyme

Abstract

An analog of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, was synthesized in which the amide bond connecting phenylalanine and glycine was replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I 50 [mean inhibitory concentration] = 0.07 .mu.M, than Bz-Phe-Gly-Pro, I50 = 9.4 .mu.M, or than the orally active D-3-mercapto-2-methylpropanoyl-L-proline (captopril, 1), I50 = 0.30 .mu.M. Compound 20 has a Ki of 1.06 .times. 10-7 and competitive or noncompetitive enzyme kinetics depending on what substrate is used in the converting enzyme assay. In tests for inhibition of angiotensin I induced contractions in the guinea pig ileum, 20 has 1/10 the activity of 1. [Blood pressure regulation is discussed.].