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

An analogue of a tripeptide inhibitor of angiotensin converting enzyme, Bz-Phe-Gly-Pro, has been synthesized in which the amide bond connecting phenylalanine and glycine has been replaced by a ketomethylene group. This nonpeptide analogue, 20, shows more potent converting enzyme inhibiting activity, I50 = 0.07 microM, than Bz-Phe-Gly-Pro, I50 = 9.4 microM, or than the orally active D-3-mercapto-2-methylpropanoyl-L-proline (captopril, 1), I50 = 0.30 microM. Compound 20 has a Ki of 1.06 X 10(-7) and either 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 one-tenth the activity of 1.