Biochemical and pharmacological characterization of ICI 186,756: a novel, potent, and selective inhibitor of human neutrophil elastase.
ICI 186,756 is a representative of a new chemical class of synthetic inhibitors of human neutrophil elastase (HNE). This compound demonstrated competitive inhibition of HNE with a Ki of 3.6 +/- 0.8 x 10(-9) mol/L. The selectivity of ICI 186,756 for HNE versus a variety of enzymes ranged from a minimum of 870-fold to greater than 640,000. The compound effectively inhibited hydrolysis of bovine ligamentum nuchae elastin by HNE. Pretreatment of hamsters with ICI 186,756 up to 2 h before intratracheal administration of HNE inhibited enzyme-induced increases in lung weight, total lavageable red cells, and total lavageable white cells measured 24 h after HNE administration. In contrast, similar lung effects produced by intratracheal administration of porcine pancreatic elastase (PPE) were not inhibited by ICI 186,756. Treatment of hamsters with 43 mumol/kg (sc) of ICI 186,756 for 14 or 28 days modulated the increases in alveolar diameter produced by both PPE and HNE, respectively. It is concluded that ICI 186,756 is a potent, competitive, and selective inhibitor of HNE that may be useful in understanding the role of this enzyme in animal models of various diseases. Furthermore, the maintenance or progression of emphysema-like lesions induced in hamsters by PPE do not appear to be due to the persistence of that enzyme within the lung.
Department of Pharmacology, ICI Americas, Inc., Wilmington, Delaware 19897.
J C
JC
Williams
R L
RL
Stein
A M
AM
Strimpler
B
B
Reaves
R D
RD
Krell
D000818:Animals; D006224:Cricetinae; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D008647:Mesocricetus; D009504:Neutrophils / Q000201:enzymology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000517:prevention & control; D013552:Swine
D009842:Oligopeptides; C071707:ICI 186756; D010196:Pancreatic Elastase