title: Biochemical and pharmacological characterization of FK706, a novel elastase inhibitor.
abstract: FK706, sodium 2-[4-[[(S)-1-[[(S)-2-[[(RS)-3, 3, 3-trifluoro-1-isopropyl-2-oxopropyl]aminocarbonyl]pyrrolidin -1-yl]carbonyl]-2-methylpropyl] aminocarbonyl] benzoylamino] acetate, C26H32F3N4NaO7, is a synthetic water-soluble inhibitor of human neutrophil elastase. This compound demonstrated a competitive and slow-binding inhibition of human neutrophil elastase with a Ki of 4.2 nM. In studies using synthetic substrates, FK706 inhibited human neutrophil elastase activity and porcine pancreatic elastase activity with respective IC50 values of 83 and 100 nM. FK706, however, inhibited more weakly, (IC50 values > 340 microM) other serine proteinases such as human pancreatic alpha-chymotrypsin, human pancreatic trypsin and human leukocyte cathepsin G. FK706 also effectively inhibited the hydrolysis of bovine neck ligament elastin (2 mg/ml final concentration) by human neutrophil elastase (4 microg/ml final concentration) with an IC50 value of 230 nM. FK706 protected animals against human neutrophil elastase (50 microg/animal)-induced lung hemorrhage with ED50 values of 2.4 microg/animal by intratracheal administration and 36.5 mg/kg by intravenous administration, respectively. Subcutaneous administration of FK706 significantly suppressed human neutrophil elastase (20 microg/paw)-induced paw edema in mice in a dose-dependent manner (47% inhibition at a dose of 100 mg/kg). These results suggest that FK706 would be a useful tool for investigating the role of human neutrophil elastase in inflammatory disorders associated with an excess of elastase, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, chronic bronchitis and rheumatoid arthritis.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan. yasuhikovshinguh@rnd.fujisawa.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Shinguh
authors.forename: K
authors.initials: K
authors.lastname: Imai
authors.forename: A
authors.initials: A
authors.lastname: Yamazaki
authors.forename: N
authors.initials: N
authors.lastname: Inamura
authors.forename: I
authors.initials: I
authors.lastname: Shima
authors.forename: A
authors.initials: A
authors.lastname: Wakabayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Higashi
authors.forename: T
authors.initials: T
authors.lastname: Ono
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011480:Protease Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: D001565:Benzoates; C109799:FK 706; D011480:Protease Inhibitors; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D019272:Leukocyte Elastase