title: Biochemical and pharmacological characterization of FR134043, a novel elastase inhibitor.
abstract: FR134043, disodium(Z,1S,15S,8S,24S,27R,29S,34S,37R)-29-ben zyl-21-ethylidene-27-hydroxy-15-isobutyrylamino-34-isopropyl-31,37 -dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,28, 31,33-octaazatetracyclo[16.13.6.1(24),(28).0(3),(8)]octatricont a-3,5,7-trien-5,6-diyl disulfate, is a water-soluble inhibitor of human neutrophil elastase with a molecular mass of 1166.15 Da. FR134043 demonstrated a characteristic competitive inhibition of human neutrophil elastase with a Ki of 8 nM. In studies using synthetic substrates, FR134043 inhibited both neutrophil elastase activity and porcine pancreatic elastase activity with IC50 values of 35 nM and 49 nM respectively. FR134043 also inhibited hydrolysis of bovine neck ligament elastin by human neutrophil elastase with an IC50 value of 210 nM. In in vivo experiments, FR134043 protected animals against human neutrophil elastase (50 microg/animal)-induced lung hemorrhage in hamsters with an ED50 value of 3.1 microg/animal for intratracheal administration and 5.0 mg/kg for intravenous administration. Subcutaneous treatment with FR134043 significantly suppressed human neutrophil elastase (20 microg/paw)-induced paw edema in mice with an ED50 value of 3.3 mg/kg when evaluated 4 h after elastase injection. The potency of FR134043 given intratracheally to protect against porcine pancreatic elastase (100 microg/animal)-induced emphysema in hamsters was relatively low (Quasi-static lung compliance; ED50 = 1590 microg/animal) compared to that in acute animal models. FR134043 (10 mg/kg per h i.v. infusion) significantly improved lipopolysaccharide (0.25 mg/kg per h i.v. infusion)-induced thrombocytopenia and some coagulation parameters in rats. These results suggest that systemic administration of FR134043 would be advantageous over intratracheal administration of FR134043 for the treatment of adult respiratory distress syndrome, septic shock and pulmonary emphysema and other pathophysiologic conditions in which elastases are thought to be involved.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical, Ibaraki, Japan. yasuhikovshinguh@rnd.fujisawa.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Shinguh
authors.forename: A
authors.initials: A
authors.lastname: Yamazaki
authors.forename: N
authors.initials: N
authors.lastname: Inamura
authors.forename: K
authors.initials: K
authors.lastname: Fujie
authors.forename: M
authors.initials: M
authors.lastname: Okamoto
authors.forename: K
authors.initials: K
authors.lastname: Nakahara
authors.forename: Y
authors.initials: Y
authors.lastname: Notsu
authors.forename: M
authors.initials: M
authors.lastname: Okuhara
authors.forename: T
authors.initials: T
authors.lastname: Ono
mesh_terms: D000818:Animals; D002417:Cattle; D006224:Cricetinae; D004211:Disseminated Intravascular Coagulation / Q000503:physiopathology; D004487:Edema / Q000188:drug therapy / Q000473:pathology; D004646:Emphysema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013552:Swine
chemical_list: C094461:FR 134043; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D015842:Serine Proteinase Inhibitors; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase