Latent inhibitors. Part 9. Substrate activated time-dependent inhibition of carboxypeptidase A by aminocyclopropanecarboxylic acid derivatives and analogues

Abstract

A series of 1-aminocyclopropanecarboxylic acid derivatives and analogues have been synthesised as potential inhibitors of carboxypeptidase A. Whereas simple cyclopropylcarboxamido derivatives of Gly, Phe and Pro showed no indications of time-dependent, irreversible inhibition, benzamido-1-aminocyclopropane carboxamido-Phe and Pro were characterised as latent inhibitors. The former was also a substrate for carboxypeptidase A but the latter was purely an inhibitor. This behaviour suggested that cyclopropylketones should also be inhibitors of carboxypeptidase A; this suggestion was confirmed experimentally. Kinetic experiments showed surprisingly that the rate of inhibition is increased in the presence of substrate, hippurylphenylalanine. Related secondary alcohols also acted as time-dependent inhibitors. The results are evaluated in the context of current views on the mechanism of action of carboxypeptidase A.