Acylating Agents as Enzyme Inhibitors and Understanding Their Reactivity for Drug Design

Nicholas O. Sykes, Simon J F Macdonald, Michael I. Page

Research output: Contribution to journalArticle

33 Citations (Scopus)


A series of bicyclic trans-fused γ-lactones and γ-lactams have been previously described for the inhibition of human neutrophil elastase and as possible development candidates. During the discovery program, it had been assumed that their acylating power was due in part to the inherent strain energy in the bicyclic structure that was released upon ring opening. This is now shown not to be the case, and in fact, these compounds are no more reactive than simple but analogous γ-lactams and γ-lactones. The strain energy is not released in the transition state for alkaline hydrolysis or alcoholysis because the reaction proceeds with rate-limiting formation of the tetrahedral intermediate. A reactivity index of kOH is proposed as a simple guide to determine the usefulness of a potential inhibitor as an enzyme acylating agent.

Original languageEnglish
Pages (from-to)2850-2856
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number13
Early online date24 May 2002
Publication statusPublished - 20 Jun 2002


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