Inhibition of human neutrophil elastase by ICI 200,355.
To examine the pathogenetic role of neutrophil elastase in airway hypersecretion, we have studied the novel inhibitor of this enzyme, [4-(4-bromophenylsulfonylcarbamoyl)benzoyl-L-valyl-L-proline 1 (RS)-(1-trifluroacetyl-2-methylprolyl)amide] (ICI 200, 355). This compound was a potent (Ki = 0.6 +/- 0.22 nM) inhibitor of human neutrophil elastase and a much weaker inhibitor of other hydrolases. ICI 200,355 also inhibited the ongoing destruction of insoluble elastin by human neutrophil elastase. ICI 200,355 produced a concentration-dependent inhibition of the secretory response induced by human neutrophil elastase (10(-8) M), with an IC50 of 1.6 x 10(-8) M. ICI 200,355 had no effect on baseline secretion or on the secretory response to chymase, cathepsin G or Pseudomonas aeruginosa elastase. Thus, ICI 200,355 appears to be a useful tool for investigating the role of human neutrophil elastase in inflammatory disorders associated with hypersecretion, such as cystic fibrosis, chronic bronchitis, and asthma.
Sommerhoff
C P
CP
Cardiovascular Research Institute, University of California, San Francisco 94143.
Krell
R D
RD
Williams
J L
JL
Gomes
B C
BC
Strimpler
A M
AM
Nadel
J A
JA
D004549:Elastin / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D006868:Hydrolysis; D009504:Neutrophils / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*
D009842:Oligopeptides; C069366:ICI 200355; D004549:Elastin; D006867:Hydrolases; D010196:Pancreatic Elastase