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

Alison Kemp, Surjit K. Ner, Lilias Rees, Colin J. Suckling, M. Catriona Tedford, Andrew R. Bell, Roger Wrigglesworth

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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.
Original languageEnglish
Pages (from-to)741-748
Number of pages8
JournalJournal of the Chemical Society, Perkin Transactions 2
Volume1993
Issue number4
DOIs
Publication statusPublished - Apr 1993

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