4-ACYLAMINOPHENOL DERIVATIVES AS NOVEL LIPOXYGENASE INHIBITORS - SYNTHESIS AND INHIBITORY EFFECT ON 5-LIPOXYGENASE AND LEUKOTRIENE B-4 PRODUCTION

Structure-activity relationships in the inhibitory effects of 4-acylam inophenol derivatives es on the 5-lipoxygenase (5-LOX) from RBL-1 cell s and leukotriene B-4 (LTB(4)) production by guinea pig neutrophils we re studied. When the N-acyl group was n-octanoyl or 2-thiophenecarbony l 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 e nzymatic and cellular systems. Among the 2,6-dimethyl derivatives with an acyl group of various carbon-chain lengths (C-1-13), those with a n-alkyl chain of C-5 to C-12 showed similarly potent inhibitory activi ties toward 5-LOX with an IC50 ranging from 0.27 to 0.66 mu M; in cont rast, maximal inhibitory activities toward LTB(4) production were obse rved 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 fa r the most inhibitory group of the series and the inhibitory activity sharply decreased on either side of the chain length. Nearly all the a ctive compounds also inhibited cyclooxygenase (COX), but the IC50 valu es for COX inhibition were more than ten times higher than the corresp onding IC50 values for 5-LOX inhibition in most cases, indicating that the acylaminophenols are relatively selective 5-LOX inhibitors.