IN-VITRO PHARMACOLOGY OF BAY-X1005, A NEW INHIBITOR OF LEUKOTRIENE SYNTHESIS

BAY X1005, -2-4-(quinolin-2-yl-methoxy)phenyl!-2-cyclopentyl acetic a cid, is an enantioselective inhibitor of leukotriene biosynthesis. It effectively inhibits the synthesis of LTB4 in A23187-stimulated leukoc ytes from rats, mice and humans (IC50 0.026, 0.039 and 0.22 mumol/l, r espectively) as well as the formation of LTC4 (IC50 0.021 mumol/l) in mouse peritoneal macrophages stimulated with opsonized zymosan. The co mpound is, however, less active in inhibiting LTB4 synthesis in human whole blood (IC50 17.0 and 11.6 mumol/l, as measured by RIA or HPLC, r espectively). BAY X1005 exhibits a high enantioselectivity in human wh ole blood (31 times over the (S)-enantiomer). BAY X1005 is shown to be a selective inhibitor of the formation of 5-lipoxygenase-derived meta bolites in vitro, without effects on other routes of arachidonic acid metabolism such as 12-lipoxygenase in human whole blood and cyclooxyge nase in both mouse macrophages and human whole blood. BAY X1005 is dev oid of any antioxidant activity (methemoglobin induction and xanthine- xanthine oxidase assay), without effects on granule release and with o nly weak effects on reactive oxygen species generation in human PMNL.