Biochemical Characterization of α-Ketooxadiazole Inhibitors of Elastases

Biochemical Characterization of α-Ketooxadiazole Inhibitors of Elastases

A series of α-ketooxadiazole compounds was prepared and evaluated in vitro as potential inhibitors of human neutrophil elastase (HNE), proteinase-3 (PR-3), and porcine pancreatic elastase (PPE). Several compounds have been found to be very potent, fast, reversible, and selective inhibitors of HNE wi...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics Vol. 367; no. 2; pp. 193 - 201
Main Authors: Wieczorek, Maciej, Gyorkos, Albert, Spruce, Lyle W., Ettinger, Anna, Ross, Sherman E., Kroona, Heather S., Burgos-Lepley, Carmen E., Bratton, Larry D., Drennan, Tyler S., Garnert, Douglas L., Von Burg, Gregory, Pilkington, Carolyn G., Cheronis, John C.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 15-07-1999
Subjects:
Cathepsin G
Cathepsin L
Cathepsins - metabolism
Chymotrypsin - metabolism
Cysteine Endopeptidases
elastase inhibitors
Endopeptidases
human neutrophil elastase
Humans
Kinetics
Leukocyte Elastase - antagonists & inhibitors
myeloblastin
Oxadiazoles - chemical synthesis
Oxadiazoles - chemistry
Oxadiazoles - pharmacokinetics
Pancreas - enzymology
proteinase-3
Serine Endopeptidases
α-ketooxadiazole
myeloblastin
α-ketooxadiazole
human neutrophil elastase
proteinase-3
elastase inhibitors
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Summary:A series of α-ketooxadiazole compounds was prepared and evaluated in vitro as potential inhibitors of human neutrophil elastase (HNE), proteinase-3 (PR-3), and porcine pancreatic elastase (PPE). Several compounds have been found to be very potent, fast, reversible, and selective inhibitors of HNE with Ki values below 100 pM. The highest kon value exceeded 107 M−1 s−1. Some α-ketooxadiazoles were also very effective against PR-3 and PPE with Ki values in the range of 5–10 nM and 0.1–2 nM, respectively. The two rings, 1,2,4- and 1,3,4-oxadiazole, are amenable to substitutions, extending the P′ side of the inhibitor and allowing additional binding interactions at S′ subsites of the enzyme. Nonpeptidic HNE inhibitors containing the oxadiazole heterocycle displayed promising oral bioavailability.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0003-9861
1096-0384
DOI:10.1006/abbi.1999.1249