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.