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 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.
Edwards
P D
PD
Department of Medicinal Chemistry, ZENECA Pharmaceuticals, Wilmington, Delaware 19897.
Wolanin
D J
DJ
Andisik
D W
DW
Davis
M W
MW
D000595:Amino Acid Sequence; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D019272:Leukocyte Elastase; D008875:Middle Aged; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D007659:Ketones; D010455:Peptides; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase