title: Structure-activity relationships leading to WAY-121,520, a tris aryl-type, indomethacin-based, phospholipase A2 (PLA2)/leukotriene biosynthesis inhibitor.
abstract: We were intrigued by reports of the inhibition of phospholipase A2 (PLA2) by indomethacin. In order to increase the potency of the indomethacin system as an inhibitor of PLA2, it was decided to make more lipophilic analogs. Indeed, covalent attachment of a quinoline ring to the methoxy substituent of indomethacin affords WAY-122,220 which is almost an order of magnitude more potent than indomethacin in inhibiting human synovial fluid PLA2 (IC50 = 15 and 145 microM, respectively). The N-p-chloro-benzyl analog of this compound, WAY-121,520, was an even more potent inhibitor of PLA2 (IC50 = 4 microM). Structural analyses and molecular modeling suggest that these compounds may inhibit PLA2 by mimicking arachidonic acid. WAY-121,520 is also a potent leukotriene biosynthesis inhibitor both in the rat PMN and mouse macrophage assays (IC50 = 10 and 4 nM, respectively), possibly acting via a 5-LO (5-lipoxygenase) translocation inhibition mechanism. The multiple actions of WAY-121,520 may contribute to its favorable anti-inflammatory profile.
authors.affiliation: Wyeth-Ayerst Research, Princeton, NJ 08543-8000.
authors.forename: A
authors.initials: A
authors.lastname: Kreft
authors.forename: J
authors.initials: J
authors.lastname: Nelson
authors.forename: J
authors.initials: J
authors.lastname: Musser
authors.forename: A
authors.initials: A
authors.lastname: Failli
authors.forename: U
authors.initials: U
authors.lastname: Shah
authors.forename: D
authors.initials: D
authors.lastname: Kubrak
authors.forename: A
authors.initials: A
authors.lastname: Banker
authors.forename: R
authors.initials: R
authors.lastname: Steffan
authors.forename: G
authors.initials: G
authors.lastname: Schiehser
authors.forename: R
authors.initials: R
authors.lastname: Sturm
mesh_terms: D000818:Animals; D016861:Cyclooxygenase Inhibitors; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013582:Synovial Fluid / Q000187:drug effects / Q000201:enzymology
chemical_list: D016861:Cyclooxygenase Inhibitors; D015289:Leukotrienes; D011804:Quinolines; C085020:WAY 121520; D010741:Phospholipases A; D054467:Phospholipases A2; D007213:Indomethacin