The leukotrienes (LTs) are potent lipid mediators, derived from arachidonic acid (AA), that historically have been implicated in a variety of inflammatory diseases including asthma and allergy [1,2]. In the last 20 years, much research has been aimed at discovering selective inhibitors of the various enzymes involved in the biosynthetic pathway leading from AA to the LTs (including 5-lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP), LTA4 hydrolase and LTC4 synthase) since such inhibition holds promise for therapeutic intervention in diseases characterized by LT mediated inflammation. To date, however, zileuton is the only inhibitor of an enzyme in this pathway, 5-LO, to be approved as a therapeutic agent for the treatment of asthma and this occurred in late 1996. More recently, the involvement of LTs in the inflammatory component of various cancers [3,4] and atherosclerosis [5-7] has been studied and the link to these clinical indications has rekindled interest in the discovery of inhibitors of LT synthesis.
A growing body of literature has accompanied this renewed interest in the LT pathway. Since the subject was last reviewed in this forum in 1997 , comprehensive reviews on the biochemistry [9,10], pharmacology [11,12], and inhibitors of
ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 40 ISSN: 0065-7743 DOI 10.1016/S0065-7743(05)40013-5
© 2005 Elsevier Inc. All rights reserved
5-LO and FLAP [2,13-15] have been published. Reviews on the biochemistry [16,17] and inhibitors  of LTA4 hydrolase have appeared. Although there have been no reports of new LTC4 synthase inhibitors, the biochemistry of this enzyme has been reviewed [19,20]. In addition, a number of reviews have summarized recent developments in the chemistry and biology of dual 5-LO/cyclooxygenase (COX) inhibitors [21-25].
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If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.