New Class of 5-Lipoxygenase Inhibitors: Correlation Between Inhibition of LTB4 Production and Chemiluminescence of...

The effect of several series of compounds on the biosynthesis of leukotriene B4 in human polymorphonuclear granulocytes (PMNL) was measured after stimulation of the cells by the Ca(2+) ionophore A23187. Phenylhydrazone derivatives and some pyrrole derivatives strongly inhibited 5-lipoxygenase activity at 10 µM. In contrast, 4-aminopyrrolopyrimidines and 4-oxopyrrolopyrimidmes did not exhibit any effect. The compounds examined for inhibition of 5-lipoxygenase were also tested in a chemiluminescence assay for potential effects on the emission of photons as a measure of activated oxygen species generated by the stimulated granulocytes. There was a good correlation between lipoxygenase inhibition and suppression of chemiluminescence; however, some derivatives with no inhibitory activity against lipoxygenase still reduced chemiluminescence, which suggests that an alternative inhibitory mechanism of chemiluminescence must be present. Cyclooxygenase inhibitors such as aspirin did not suppress chemiluminescence of granulocytes. It is, therefore, unlikely that cyclooxygenase is required in the chemiluminescence reaction. In contrast, LTB4 seems to play an important role in the zymosan-induced chemiluminescence of PMNL.