Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo^®), currently the only approved and clinically used 5‐Lipoxygenase (5‐LO) inhibitor, the search for potent and safe 5‐LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5‐Lipoxygenase (5‐LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5‐LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated. The shortening of the linker between the carbonyl and the catechol moiety as well as the presence of the α,β‐unsaturated carbonyl group was also explored. The sinapic acid phenethyl ester (10), which can be named SAPE (10) by analogy to caffeic acid phenethyl ester (CAPE), inhibited 5‐LO in a concentration‐dependent manner and outperformed both zileuton (1) and CAPE (2). With an IC₅₀ of 0.3 μm, SAPE (10) was threefold more potent than CAPE (2) and 10‐fold more potent than zileuton (1), the only 5‐LO inhibitor approved for clinical use. Unlike CAPE (2), SAPE (10) had no effect on 12‐lipoxygenase (12‐LO) and less effect on cyclooxygenase 1 (COX‐1) which makes it a more selective 5‐LO inhibitor.

中文翻译：

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芥子酸苯乙酯作为一种有效的选择性5-脂氧合酶抑制剂：合成与结构-活性关系

由于肝毒性和齐留通（Zyflo的不利的药物代谢动力学曲线^®），目前唯一批准用于临床5-脂氧合酶（5-LO）抑制剂，有效和安全的5-LO抑制剂的研究是非常需要的。已经研究了几种酚酸苯乙酯作为潜在的5-Lipoxygenase（5-LO）抑制剂的作用。为此目的，合成了一系列14种苯乙酯，并评估了它们对5-LO抑制的影响。研究了羟基和甲氧基的位置和数量对酚酸的影响。还研究了羰基和邻苯二酚部分之间连接基的缩短以及α，β-不饱和羰基的存在。芥子酸苯乙酯（10）（类似于咖啡酸苯乙酯（CAPE））可以命名为SAPE（10），它以浓度依赖的方式抑制5-LO，并且优于zileuton（1）和CAPE（2）。随着集成电路的₅₀ 0.3μ的米，SAPE（10）有三个比CAPE（更有效2）和10倍齐留通（更有效1），批准用于临床使用的唯一5-LO抑制剂。与CAPE（2）不同，SAPE（10）对12-脂氧合酶（12-LO）没有影响，而对环氧合酶1（COX-1）的作用较小，这使其成为更具选择性的5-LO抑制剂。