Neutrophil elastase inhibitors as treatment for COPD.
Chronic obstructive pulmonary disease, characterised by a slowly progressive, irreversible airways limitation, is a major worldwide cause of chronic morbidity and mortality. The imbalance between human neutrophil elastase and endogenous antiproteases may cause excess human neutrophil elastase in pulmonary tissues, which may be considered a major pathogenic factor in chronic obstructive pulmonary disease. Great effort has been devoted to finding a method to restore the balance, resulting in the discovery of potent two-typed small-molecular-weight human neutrophil elastase inhibitors. In the application of chronic obstructive pulmonary disease therapy, the human neutrophil elastase inhibitors mainly focused upon include ONO-5046, MR-889, L-694,458, CE-1037, GW-311616 and TEI-8362 as the acyl-enzyme inhibitors; and ONO-6818, AE-3763, FK-706, ICI-200,880, ZD-0892 and ZD-8321 as the transition-state inhibitors. In this review, various problems that remain to be solved in the clinical use of human neutrophil elastase inhibitors are discussed.
Ohbayashi
Hiroyuki
H
Internal Medicine II, Nagoya University School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya city, 466-8550, Japan. ohbayasi@nn.iij4u.or.jp
D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology; D009504:Neutrophils / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D015843:Serpins / Q000627:therapeutic use*; D012907:Smoking / Q000009:adverse effects
D011480:Protease Inhibitors; D015843:Serpins; D019272:Leukocyte Elastase