Biochemistry and pharmacology of ICI 200,880, a synthetic peptide inhibitor of human neutrophil elastase.

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.