Pharmacological Inhibitors of Cysteinyl Leukotrienes Biosynthesis: Therapeutic Implications

Cysteinyl leukotrienes (cys-LTs) have emerged as important mediators of inflammation. Interest in these molecules have been amplified by recent introduction of the drugs which can either inhibit their biosynthesis or interfere with their binding to specific receptors. Biosynthesis of cys-LTs starts with the action of 5-lipoxygenase on arachidonic acid, liberated from membrane phospholipids and leads to formation of leukotriene A4 (LTA4). Cells, which express leukotriene C4 synthase (LTC4S), conjugate LTA4 with reduced glutathione to leukotriene C4 (LTC4), the first derivative of the family of cysteinyl leukotrienes. This in turn can be converted to leukotriene D4 (LTD4) and then to leukotriene E4 (LTE4). Cys-LTs powerfully affect cardiopulmonary functions. Thus, they contribute to bronchoconstriction, mucous secretion, edema migration of eosinophils into airways, and constriction of vessels including coronary arteries. A welldefined clinical syndrome, which affects about 10 % of adult asthmatics, i.e. called aspirin-induced asthma (AIA), is characterized by overproduction of cys-LTs. Chronic treatments of AIA patients with leukotriene biosynthesis inhibitors produce clinical benefits and improvement in pulmonary function tests. 5-LO inhibitors can be classified into several classes of compounds; redox, and non-redox inhibitors, first and second generation N-hydroxyurea derivatives, and FLAP inhibitors. From the clinical point of view, the most important group of inhibitors are the first N-hydroxyurea derivatives e.g. zileuton. They show clinical efficacy in asthma and provide a rationale for envisioning novel leukotriene - based approaches in therapy.