Structure activity analysis of the pyridazinone series as represented by the initial lead compound A-53612 revealed that the 1-phenyl-2H-tetrahydropyridazin-3-one structure was necessary for inhibitory activity as several modifications diverging from this structure led to a dramatic loss of inhibitory activity. Substituents on the phenyl ring had a marked effect on inhibitory activity and methemoglobinemia toxicity.Inhibition of leukotriene biosynthesis by inhibition of the enzyme 5lipoxygenase @LO) represents a promising new therapeutic intervention.1 The discovery of A-53612, 1-phenyl-[2H]-tetrahydropyridazin-3-one as a selective orally active 5-LO inhibitor provided a lead compound for further optimization.2 This report describes the structure-activity relationships of this series of 5-LO inhibitors.