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.
Williams
J C
JC
Department of Pharmacology, ICI Americas, Inc., Wilmington, Delaware 19897.
Stein
R L
RL
Strimpler
A M
AM
Reaves
B
B
Krell
R D
RD
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