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

Abstract

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®, 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 date, however, no clear advantage for inhibitors of lipoxygenase has been demonstrated relative to the leukotriene D 4 receptor antagonists such as Singulair® and Accolate®.