Inhibitory Effect of 4-Acylaminophenol Derivatives (T-0799 and T-0757), Novel Lipoxygenase Inhibitors, on Arachidonic Acid-Induced Infiltration of Polymorphonuclear Leukocytes in Rat Skin

Abstract

ABSTRACT-Effects of 4-acylaminophenol derivatives, novel 5-lipoxygenase inhibitors, on the neutrophil infiltration in arachidonic acid (AA) (10 mg/site)-induced skin inflammation in rats were examined. Myeloperoxidase (MPO) activity in the skin lesion, used as an indicator of neutrophil infiltration, was significantly increased after intradermal injection of AA. Dual inhibitors of cyclooxygenase and 5-lipox ygenase, phenidone (100 mg/kg x 2, i.p. and p.o.) and BW-755C (50 mg/kg x 2, p.o.), and 5-lipoxygenase inhibitors, AA-861 (100 mg/kg x 2, i.p.) and the 4-acylaminophenol derivatives T-0799 and T-0757 (10-100 mg/kg x 2, p.o.), inhibited the increase in MPO activity 5 hr after AA-injection, but the cycloox ygenase inhibitor indomethacin (5 mg/kg, i.p.) showed no effect. These results suggest that products of lipoxygenase, but not of cyclooxygenase, are involved in the MPO activity increase (i.e., neutrophil infiltra tion), and that this model is useful for in vivo evaluation of 5-lipoxygenase inhibitors. It is suggested that the 4-acylaminophenol derivatives may be useful as orally active drugs for treatment of some leukotriene mediated diseases.

Involvement of leukotrienes in allergic pleurisy in actively sensitized rats: Inhibition by the lipoxygenase inhibitor T-0757 of the increase in vascular permeability and leukotriene E4 production

“…We have previously reported that T-0757, a 4-acylaminophenol derivative, inhibits 5-1ipoxygenase activity in vitro [14], and that, on oral administration to rats, it inhibits neutrophil infiltration in arachidonic acidinduced skin inflammation [15] and prevents both LTB 4 production and leukocyte infiltration in zymosan-induced inflammation [16].…”