5-Lipoxygenase: properties, pharmacology, and the quinolinyl(bridged)aryl class of inhibitors

Abstract

In conclusion, an effective modulator of the AA cascade for the treatment of asthma and other inflammatory diseases may require 5-LO inhibitory activity as well as LTD4 antagonism in order to limit the effects of LTB4, LTD4, and 5-HPETE. The unknown role of LTC4 with respect to bronchoconstriction and mucus production could mask the efficacy of a pure LTD4 antagonist in man, whereas the chemotactic property of LTB4 for eosinophils can contribute to lung inflammation. Indeed, it is observed that the blood of patients with bronchial asthma has increased numbers of hypodense eosinophils. In addition, the formation of lipid-derived peroxide radicals, such as 5-HPETE, are believed to be responsible for various types of cellular injuries associated with the inflammatory disease process. Because inhibition of the CO pathway is thought to explain the therapeutic effects of nonsteroidal antiinflammatory agents in rheumatic diseases, a 5-LO inhibitor with CO inhibitory activity may also be desirable profile for an antiasthma agent. The validation of the LT hypothesis of disease had to wait for the demonstration of a clinical effect by either a LTD4 receptor antagonist or a LT synthesis inhibitor (5-LO inhibitor). Only very recently has this evidence become available and it is now apparent that compounds that antagonize LTD4 receptors or inhibit LT synthesis have shown clinical efficacy in a wide range of diseases. Due to the breakthrough nature of this approach, certain of these compounds are being considered for expedited development. The absence of side effects seen in the clinical trials of selective 5-LO inhibitors is gratifying and argues that LTs are not important in homeostasis. Only time will tell whether 5-LO inhibitors will take their place in the therapeutic armamentarium; however, the recent demonstration of clinical efficacy by a number of these compounds is a significant step in this direction.