title: Pharmacological characterization of WAY-121,520: a potent anti-inflammatory indomethacin-based inhibitor of 5-lipoxygenase (5-LO)/phospholipase A2 (PLA2).
abstract: WAY-121,520 inhibited human synovial fluid PLA2 (HSF-PLA2) (IC50 = 4 microM) using arachidonic acid-labeled E. coli as substrate. Further biochemical characterization of WAY-121,520 demonstrated potent inhibition of 5-lipoxygenase (5-LO) activity in the murine macrophage (LTC4, IC50 = 4 nM) and rat PMN (LTB4, IC50 = 10 nM) and an ability to antagonize LTD4 binding to isolated guinea-pig trachea (pKB = 6.0). In vivo anti-inflammatory activity was noted in murine TPA-induced (ED50 = 91 micrograms/ear) and arachidonic acid-induced (66% inhibition at 400 micrograms/ear) ear edema and in leukotriene-dependent antigen-induced bronchoconstriction in the guinea pig (73% inhibition at 50 mg/kg, p.o.). WAY-121,520 represents a novel series of indomethacin-based inhibitors of PLA2 with anti-inflammatory activity resulting from a combination of biochemical activities (inhibition of 5-LO and PLA2 and LTD4 antagonism). This agent may provide added therapeutic efficacy over more selective inhibitors.
authors.affiliation: Wyeth-Ayerst Research, Princeton, NJ 08543.
authors.forename: K B
authors.initials: KB
authors.lastname: Glaser
authors.forename: R P
authors.initials: RP
authors.lastname: Carlson
authors.forename: A
authors.initials: A
authors.lastname: Sung
authors.forename: J
authors.initials: J
authors.lastname: Bauer
authors.forename: Y W
authors.initials: YW
authors.lastname: Lock
authors.forename: D
authors.initials: D
authors.lastname: Holloway
authors.forename: R
authors.initials: R
authors.lastname: Sturm
authors.forename: D
authors.initials: D
authors.lastname: Hartman
authors.forename: T
authors.initials: T
authors.lastname: Walter
authors.forename: S
authors.initials: S
authors.lastname: Woeppel
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D004487:Edema / Q000188:drug therapy; D006168:Guinea Pigs; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000096:biosynthesis; D011458:Prostaglandins E / Q000096:biosynthesis; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011458:Prostaglandins E; D011804:Quinolines; C085020:WAY 121520; D010741:Phospholipases A; D054467:Phospholipases A2; D007213:Indomethacin