Biologic characterization of ICI 200,880 and ICI 200,355, novel inhibitors of human neutrophil elastase.
ICI 200,880 and its close structural analog, ICI 200,355, are representatives of a new chemical class of inhibitors of human neutrophil elastase (HNE). Both compounds are substituted tripeptide ketones, which demonstrated competitive kinetics versus HNE, with identical Ki values of 5.0 x 10(-10) M. The selectivity of ICI 200,880 for HNE versus a variety of enzymes ranged from 150-fold [relative to porcine pancreatic elastase (PPE)] to greater than 360,000-fold in favor of HNE. The compound effectively inhibited HNE-hydrolysis of bovine ligamentum nuchae elastin. In pharmacokinetic studies, ICI 200,880 and ICI 200,355 displayed long retention times when administered directly to the lung and were rapidly eliminated after intravenous administration. Pretreatment of hamsters with either inhibitor before intratracheal administration of HNE produced dose- and time-dependent inhibition of enzyme-induced increases in lung weight, total lavageable red cells, and total lavageable white cells. Aerosol administration of ICI 200,880 produced similar results. Subcutaneous administration of either 50 or 100 mumol/kg (twice/day) of ICI 200,880 for 14 or 28 days prevented the time-dependent increase in alveolar diameter produced by a single intratracheal dose of PPE when compound dosing was initiated 24 h after the enzyme. Treatment of hamsters with the same protocol and doses of ICI 200,880 for 8 wk prevented the destructive lesion induced by a single intratracheal dose of HNE. It is concluded that ICI 200,880 and ICI 200,355 have biochemical, pharmacokinetic, and pharmacologic profiles that make them useful therapeutic agents for understanding the role of HNE in various diseases. ICI 200,880 is presently being evaluated in humans.
Department of Pharmacology, ICI Pharmaceuticals Group, ICI Americas Inc., Wilmington, Delaware 19897.
J C
JC
Williams
R C
RC
Falcone
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Knee
R L
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Stein
A M
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Strimpler
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Reaves
R E
RE
Giles
R D
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Krell
D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004549:Elastin / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008168:Lung / Q000187:drug effects; D008297:Male; D008647:Mesocricetus; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy; D013379:Substrate Specificity / Q000187:drug effects; D013997:Time Factors
D007527:Isoenzymes; D009842:Oligopeptides; C069366:ICI 200355; C069695:ICI 200880; D004549:Elastin; D010196:Pancreatic Elastase