Abstract
WAY-121,520 inhibited human synovial fluid PLA2 (HSF-PLA2) (IC50=4 μM) using arachidonic acid-labeledE. 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=4nM) and rat PMN (LTB4, IC50=10 nM) and an ability to antagonize LTD4 binding to isolated guinea-pig trachea (pK B=6.0).In vivo anti-inflammatory activity was noted in murine TPA-induced (ED50=91 μg/ear) and arachidonic acid-induced (66% inhibition at 400 μg/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.
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Glaser, K.B., Carlson, R.P., Sung, A. et al. Pharmacological characterization of WAY-121,520: A potent anti-inflammatory indomethacin-based inhibitor of 5-lipoxygenase (5-LO)/phospholipase A2 (PLA2). Agents and Actions 39 (Suppl 1), C30–C32 (1993). https://doi.org/10.1007/BF01972711
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DOI: https://doi.org/10.1007/BF01972711