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

• Published in: European journal of medicinal chemistry Vol. 34; no. 9; pp. 671 - 685
• Main Author: Young, Robert N.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Masson SAS 01.09.1999; Elsevier
• Subjects: 5-lipoxygenase; 5-lipoxygenase activating protein; asthma; Biological and medical sciences; inflammation; inhibitor; Medical sciences; Pharmacology. Drug treatments; Respiratory system; 5-lipoxygenase activating protein; asthma; inhibitor; 5-lipoxygenase; inflammation; Sulfur nitrogen heterocycle; Iron Complexes; Oxidation reduction; Menadione; Enzyme; Nitrogen heterocycle; Antiinflammatory agent; Enzyme inhibitor; Transition metal Complexes; Review; Antiasthma agent; Oxygen heterocycle; Biological activity; Zileuton; Arachidonate 5-lipoxygenase; Chelating agent; Aromatic compound; Oxidoreductases; Mechanism of action
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(99)00225-1

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®.