Inhibitors of 5-lipoxygenase: a therapeutic potential yet to be fully realized?

Inhibition of leukotriene biosynthesis has been extensively studied as a potential for the development of novel therapies for inflammation and respiratory diseases and, in particular, for asthma. Many compounds have been identified which inhibit the key enzyme, 5-lipoxygenase. Four distinct classes of compounds have been identified, namely, (1) redox inhibitors (alternative substrates), (2) iron chelating inhibitors, (3) competitive reversible inhibitors, and (4) inhibitors of the 5-lipoxygenase activating protein. Experience over the past two decades with redox inhibitors has been disappointing and although a number of potent compounds have been identified, they have often been associated with ancillary toxicity and non-specificity due to their redox activity. Iron chelating inhibitors have been more successful and one compound, Zileuton(R), has reached the market. However, more potent analogues have often encountered toxicity problems. Competitive inhibitors have been identified by a number of research groups but, as yet, none has been successful. Inhibitors of the 5-lipoxygenase activating protein (FLAP) have been identified and compounds such as MK-0591 and BaY-X-1005 have shown efficacy in asthma trials. To dare, however, no clear advantage for inhibitors of lipoxygenase has been demonstrated relative to the leukotriene D-4 receptor antagonists such as Singulair(R) and Accolate(R). (C) 1999 Editions scientifiques et medicales Elsevier SAS.