Biochemical characterization of alpha-ketooxadiazole inhibitors of elastases.
A series of alpha-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 10(7) M(-1) s(-1). Some alpha-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.
Cortech, Inc., 6850 North Broadway, Denver, Colorado, 80221, USA. maciek@cvmbs.colostate.edu
M
M
Wieczorek
A
A
Gyorkos
L W
LW
Spruce
A
A
Ettinger
S E
SE
Ross
H S
HS
Kroona
C E
CE
Burgos-Lepley
L D
LD
Bratton
T S
TS
Drennan
D L
DL
Garnert
G
G
Von Burg
C G
CG
Pilkington
J C
JC
Cheronis
D056649:Cathepsin G; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D002918:Chymotrypsin / Q000378:metabolism; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D010179:Pancreas / Q000201:enzymology; D012697:Serine Endopeptidases
D010069:Oxadiazoles; D002403:Cathepsins; D010450:Endopeptidases; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L