Peptidyl .alpha.-ketoheterocyclic inhibitors of human neutrophil elastase. 2. Effect of varying the heterocyclic ring on in vitro potency
- 1 January 1995
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 38 (1) , 76-85
- https://doi.org/10.1021/jm00001a013
Abstract
A series of peptidyl alpha-ketoheterocycles were synthesized and evaluated for their in vitro inhibition of human neutrophil elastase (HNE). Several heterocycles, including oxazoline and benzoxazole, afforded extremely potent inhibitors of HNE (1p-r) with nanomolar to subnanomolar Ki values. The structure-activity relationships revealed that for compounds with a Ki < 1000 nM potency tends to be positively correlated with the sigma I value of the heterocycle. Furthermore, the results in this study support the hypothesis that, in the covalent enzyme-inhibitor adduct, the azole nitrogen atom of the inhibitor heterocycle participates in a hydrogen-bonding interaction with the active-site His-57.Keywords
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