title: Biochemistry and pharmacology of ICI 200,880, a synthetic peptide inhibitor of human neutrophil elastase.
abstract: ICI 200,880 is representative of a new chemical class of inhibitors of human neutrophil elastase (HNE). The compound demonstrated competitive kinetics vs HNE with a Ki value of 5.0 x 10(-10) M. The selectivity of ICI 200,880 for HNE versus a variety of enzymes ranged from 150- (relative to porcine pancreatic elastase [PPE]) to greater than 360,000-fold in favor of HNE. In pharmacokinetic studies ICI 200,880 displayed a long retention time when administered directly to the lung and was rapidly eliminated when administered intravenously. Aerosol pretreatment of hamsters with ICI 200,880 before intratracheal administration of HNE produced a long-lasting inhibition of enzyme-induced increases in lung weight, total lavageable red cells, and total lavageable white cells. 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 hours following the enzyme. Treatment of hamsters with ICI 200,880 using the same protocol and doses for 8 weeks prevented the destructive lesion induced by a single intratracheal dose of HNE. It is concluded that ICI 200,880 has biochemical, pharmacokinetic, and pharmacologic profiles that make it a useful therapeutic agent for understanding the role of HNE in various diseases. ICI 200,880 is presently being evaluated in man.
authors.affiliation: Department of Pharmacology, ICI Americas Inc., Wilmington, Delaware 19897.
authors.forename: J C
authors.initials: JC
authors.lastname: Williams
authors.forename: R L
authors.initials: RL
authors.lastname: Stein
authors.forename: R E
authors.initials: RE
authors.lastname: Giles
authors.forename: R D
authors.initials: RD
authors.lastname: Krell
mesh_terms: D000818:Animals; D006224:Cricetinae; D007700:Kinetics; D019272:Leukocyte Elastase; D008297:Male; D008647:Mesocricetus; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011656:Pulmonary Emphysema / Q000188:drug therapy
chemical_list: D009842:Oligopeptides; C069695:ICI 200880; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase