Development of 5-lipoxygenase inhibitors--lessons from cellular enzyme regulation.
5-Lipoxygenase (5-LO) catalyzes the first steps in the conversion of arachidonic acid (AA) into leukotrienes (LTs) that are mediators of inflammatory and allergic reactions. Recently, the 5-LO pathway has also been associated with atherosclerosis and osteoporosis. Thus, in addition to the classical applications including asthma and allergic disorders, LT synthesis inhibitors might be of interest for the treatment of cardiovascular diseases and osteoporosis. Recently, it has been shown that cellular 5-LO activity is regulated in a complex manner that can involve different signalling pathways. 5-LO can be activated by an increase in intracellular Ca2+ concentration, diacylglycerols, phosphorylation by MAPKAP kinase-2 and ERK. Previous work could demonstrate that cellular 5-LO activity is repressed in a protein kinase A-dependent manner and by glutathione peroxidases. This comment focuses on the impact of these stimulatory and inhibitory pathways on the efficacy of 5-LO inhibitors and suggests additional criteria for the development of this class of compounds.
Werz
Oliver
O
Institute of Pharmaceutical Chemistry/ZAFES, University of Frankfurt, Marie-Curie-Str. 9, D-60439 Frankfurt, Germany.
Steinhilber
Dieter
D
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology*; D016859:Lipoxygenase Inhibitors
D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase