Designing therapeutically effective 5-lipoxygenase inhibitors.
Metabolism of arachidonic acid by the enzyme 5-lipoxygenase leads to the formation of a group of biologically active lipids known as leukotrienes. Peptidoleukotrienes are powerful bronchoconstrictor agents while leukotriene B4 is a potent chemotactic agent for a variety of leukocytes. In view of these properties, leukotrienes have been proposed as important mediators in allergic and inflammatory disorders, and inhibitors of 5-lipoxygenase, by blocking leukotriene synthesis, have therapeutic potential in a range of diseases including arthritis and asthma. This review by Rodger McMillan and Ed Walker summarizes the biology of leukotrienes and the current knowledge of the mechanism of 5-lipoxygenase, providing a framework for consideration of the discovery, development and clinical status of drugs in the three major classes of 5-lipoxygenase inhibitors: 'redox' inhibitors, iron ligand inhibitors and 'non-redox' inhibitors.
McMillan
R M
RM
Bioscience Department 1, ICI Pharmaceuticals, Macclesfield, Cheshire, UK.
Walker
E R
ER
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D015195:Drug Design; D005290:Ferric Compounds / Q000378:metabolism; D006801:Humans; D015289:Leukotrienes / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction
D005290:Ferric Compounds; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase