Abstract
Leukotriene (LT) C4 synthase, an integral membrane protein, catalyzes the first committed step in the biosynthesis of the peptidyl leukotrienes, which have been implicated in various inflammatory disorders, including human bronchial asthma. To identify possible inhibitors of LTC4 synthase, synthetic compounds known to inhibit other proteins in the leukotriene biosynthetic pathway (5-lipoxygenase-activating protein, FLAP, and 5-lipoxygenase, 5-LO) or to antagonize leukotriene receptors (cys LT1) were tested for activity against LTC4 synthase. These assays were performed on enriched fractions of human LTC4 synthase purified from the human monocytic cell line THP-1. LTA4 and glutathione were used as substrates, and LTC4 product formation was monitored by reverse-phase high pressure liquid chromatography. Representative compounds from distinct structural classes were tested over a concentration range of 40 nM to 100 microM. The most potent inhibitor was found to be a previously established nanomolar 5-lipoxygenase inhibitor, 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)- methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]ethoxy]but anoic acid (L-699.333) of the phenylpyridine structural class of compounds. L-699....Continue Reading
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