4-Acylaminophenol Derivatives as Novel Lipoxygenase Inhibitors: Synthesis and Inhibitory Effect on 5-Lipoxygenase and Leukotriene B4 Production.

Abstract

Structure-activity relationships in the inhibitory effects of 4-acylaminophenol derivatives on the 5-lipoxygenase (5-LOX) from RBL-1 cells and leukotriene B4 (LTB4) production by guinea pig neutrophils were studied. When the N-acyl group was n-octanoyl or 2-thiophenecarbonyl and the size of the two ortho substituents of phenol was varied, the substituents bulkier than isopropyl, i.e., 2,6-di-tert-butyl and 2,6-dicyclohexyl, substantially weakened the inhibitory activity in both enzymatic and cellular systems. Among the 2,6-dimethyl derivatives with an acyl group of various carbon-chain lengths (C1-13), those with a n-alkyl chain of C5 to C12 showed similarly potent inhibitory activities toward 5-LOX with an IC50 ranging from 0.27 to 0.66 microM; in contrast, maximal inhibitory activities toward LTB4 production were observed in a narrower range of the serial compounds: i.e., those with a n-hexyl, n-heptyl, or n-octyl chain on the carbonyl carbon formed by far the most inhibitory group of the series and the inhibitory activity sharply decreased on either side of the chain length. Nearly all the active compounds also inhibited cyclooxygenase (COX), but the IC50 values for COX inhibition were more than ten times higher than the corresponding IC50 values for 5-LOX inhibition in most cases, indicating that the acylaminophenols are relatively selective 5-LOX inhibitors.

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

“…In this in vivo model of LT-mediated neutrophil infiltra tion, our novel lipoxygenase inhibitors (14), the 4-acyl aminophenol derivatives T-0799 and T-0757, were shown to be effective (Fig. 8).…”

“…We have already reported that some of the 4-acyl aminophenol derivatives are relatively selective 5-lipoxy genase inhibitors (14). The IC50 values of T-0799 for 5-lipoxygenase and cyclooxygenase were 0.81 and 140 tiM, respectively, and those of T-0757 were 0.23 and 7.0 pM, respectively.…”

“…8). Since these compounds are rela tively selective inhibitors of 5-lipoxygenase and capable of inhibiting LTB4 production (14), one of the chemo tactic factors involved in the model is likely to be LTB4. It has been reported that 5-lipoxygenase inhibitors of the redox type, such as NDGA, were inactive when ad ministered orally (19).…”

“…With this model, we evaluated the efficacies of novel lipoxygenase inhibitors, 4-acyl aminophenol derivatives (14), and compared them to those of other known inhibitors.…”

TA-270 [4-Hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1 H)-quinolinone], an Anti-Asthmatic Agent, Inhibits Leukotriene Production Induced by IgE Receptor Stimulation in RBL-2H3 Cells

“…4C, we examined whether TA-270 directly inhibits 5-lipoxygenase activity using a cell-free extract of RBL-1 basophilic cells, which express high 5-lipoxygenase activity (Kikuchi et al, 1994). To exclude the cyclooxygenase pathway, indomethacin was included in the assay medium.…”