4-acylaminophenol derivatives as novel lipoxygenase inhibitors: synthesis and inhibitory effect on 5-lipoxygenase and leukotriene B4 production.
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.
Kikuchi
M
M
Pharmacological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Hashimura
Y
Y
Tsuzurahara
K
K
Nagasawa
M
M
Inoue
H
H
Taniguchi
T
T
Uchida
T
T
D000627:Aminophenols / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D006168:Guinea Pigs; D007975:Leukotriene B4 / Q000096:biosynthesis*; D008084:Lipoxygenase / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects; D013329:Structure-Activity Relationship
D000627:Aminophenols; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D008084:Lipoxygenase