Design and synthesis of peptide-based carboxylic acid-containing transition-state inhibitors of human neutrophil elastase.
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.
Sato
Fuminori
F
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
Inoue
Yasunao
Y
Omodani
Tomoki
T
Imano
Kiyomi
K
Okazaki
Hiroshi
H
Takemura
Tadashi
T
Komiya
Masanobu
M
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
D000596:Amino Acids; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019272:Leukocyte Elastase