STRUCTURE-ACTIVITY-RELATIONSHIPS LEADING TO WAY-121,520, A TRIS ARYL-TYPE, INDOMETHACIN-BASED, PHOSPHOLIPASE A(2) (PLA2) LEUKOTRIENE BIOSYNTHESIS INHIBITOR

We were intrigued by reports of the inhibition of phospholipase A2 (PL A2) by indomethacin. In order to increase the potency of the indometha cin system as an inhibitor of PLA2, it was decided to make more lipoph ilic analogs. Indeed, covalent attachment of a quinoline ring to the m ethoxy substituent of indomethacin affords WAY-122,220 which is almost an order of magnitude more potent than indomethacin in inhibiting hum an synovial fluid PLA2 (IC50 = 15 and 145 muM, respectively). The N - p-chloro-benzyl analog of this compound, WAY-121,520, was an even more potent inhibitor of PLA2 (IC50 = 4 muM). Structural analyses and mole cular modeling suggest that these compounds may inhibit PLA2 by mimick ing arachidonic acid. WAY-121,520 is also a potent leukotriene biosynt hesis inhibitor both in the rat PMN and mouse macrophage assays (IC50 = 10 and 4 nM, respectively), possibly acting via a 5-LO (5-lipoxygena se) translocation inhibition mechanism. The multiple actions of WAY-12 1,520 may contribute to its favorable anti-inflammatory profile.