PEPTIDYL ALPHA-KETOHETEROCYCLIC INHIBITORS OF HUMAN NEUTROPHIL ELASTASE .2. EFFECT OF VARYING THE HETEROCYCLIC RING ON IN-VITRO POTENCY

A series of peptidyl alpha-ketoheterocycles were synthesized and evalu ated for their in vitro inhibition of human neutrophil elastase (HNE). Several heterocycles, including oxazoline and benzoxazole, afforded e xtremely potent inhibitors of HNE (1p-r) with nanomolar to subnanomola r K-i values. The structure-activity relationships revealed that for c ompounds with a K-i < 1000 nM potency tends to be positively correlate d with the sigma(I) value of the heterocycle. Furthermore, the results in this study support the hypothesis that, in the covalent enzyme-inh ibitor adduct, the azole nitrogen atom of the inhibitor heterocycle pa rticipates in a hydrogen-bonding interaction with the active-site His- 57.