title: Design and synthesis of peptide-based carboxylic acid-containing transition-state inhibitors of human neutrophil elastase.
abstract: In our search for a new agent, human neutrophil elastase (HNE) inhibitor, for the treatment of acute respiratory failure, we rationally designed and synthesized a series of peptide-based carboxylic acid-containing transition-state inhibitors. The presence of valyl moiety is found to be essential for potent in vitro inhibitory activity and also prevention of an undesirable toxicity. Of these, compound 9m has the most potent in vivo effect on HNE-induced lung hemorrhage in hamsters.
authors.affiliation: Department of Chemistry II, Discovery Research Laboratories, Dainippon Pharmaceutical Co., Ltd. Enoki 33-94, Suita, Osaka 564-0053, Japan. fuminori-sato@dainippon-pharm.co.jp
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sato
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Inoue
authors.forename: Tomoki
authors.initials: T
authors.lastname: Omodani
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Imano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okazaki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Takemura
authors.forename: Masanobu
authors.initials: M
authors.lastname: Komiya
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008171:Lung Diseases / Q000188:drug therapy / Q000473:pathology; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019272:Leukocyte Elastase