title: Development of a highly water-soluble peptide-based human neutrophil elastase inhibitor; AE-3763 for treatment of acute organ injury.
abstract: A series of peptide-based transition-state human neutrophil elastase (HNE) inhibitors with N-terminal acidic moieties were synthesized and their inhibitory activity against HNE was evaluated both in vitro and in vivo. Our results show that compounds containing cyclic amide bridged acidic moieties at the N-terminal have not only improved water solubility but also high in vivo potency. Among these compounds, AE-3763 showed remarkable efficacy in hamster models of elastase-induced lung hemorrhage and lipopolysaccharide (LPS)-induced lung injury as well as in a mouse model of LPS/galactosamine-induced acute multiple organ dysfunctions. The water solubility of AE-3763 (>1000 mg/ml in H(2)O) was also far superior to that of any of the other compounds synthesized. Thus, it is believed that AE-3763 would be useful for treatment of HNE-associated respiratory disorders, such as acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and acute exacerbation of chronic obstructive pulmonary disease (COPD).
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co, Ltd, Suita, Osaka 564-0053, Japan. yasunao-inoue@ds-pharma.co.jp
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Inoue
authors.forename: Tomoki
authors.initials: T
authors.lastname: Omodani
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Shiratake
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okazaki
authors.forename: Akemi
authors.initials: A
authors.lastname: Kuromiya
authors.forename: Taeko
authors.initials: T
authors.lastname: Kubo
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sato
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy*; D000818:Animals; D006224:Cricetinae; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004195:Disease Models, Animal; D005688:Galactosamine / Q000633:toxicity; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D010455:Peptides / Q000737:chemistry*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012995:Solubility
chemical_list: D004151:Dipeptides; D008070:Lipopolysaccharides; C545770:N-((3-(carboxymethyl)-2-oxoimidazolidin-1-yl)acetyl)-l-valyl-N-((3S)-1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)-l-prolinamide; D010455:Peptides; D053491:Proteinase Inhibitory Proteins, Secretory; D005688:Galactosamine; D019272:Leukocyte Elastase