Acylating agents as enzyme inhibitors and understanding their reactivity for drug design.

A series of bicyclic trans-fused gamma-lactones and gamma-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 gamma-lactams and gamma-lactones.