ONO-5046, a novel inhibitor of human neutrophil elastase.
ONO-5046, N-[2-[4-(2,2-Dimethylpropionyloxy)phenylsulfonylamino] aminoacetic acid, competitively inhibited human neutrophil elastase (IC50 = 0.044 microM, Ki = 0.2 microM). It also inhibited leukocyte elastase obtained from rabbit, rat, hamster and mouse. However, ONO-5046 did not inhibit trypsin, thrombin, plasmin, plasma kallikrein, pancreas kallikrein, chymotrypsin and cathepsin G even at 100 microM. In in vivo studies, ONO-5046 suppressed lung hemorrhage in hamster (ID50 = 82 micrograms/kg) by intratracheal administration and increase of skin capillary permeability in guinea pig (ID50 = 9.6 mg/kg) by intravenous administration, both of which were induced by human neutrophil elastase.
Kawabata
K
K
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Suzuki
M
M
Sugitani
M
M
Imaki
K
K
Toda
M
M
Miyamoto
T
T
D000818:Animals; D001667:Binding, Competitive; D002199:Capillary Permeability / Q000187:drug effects; D006224:Cricetinae; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D012871:Skin Diseases / Q000188:drug therapy; D013449:Sulfonamides / Q000494:pharmacology*
D013449:Sulfonamides; C069195:sivelestat; D010196:Pancreatic Elastase; D005998:Glycine