Discovery and Biological Evaluation of a Novel Class of Dual Microsomal Prostaglandin E2 Synthase-1/5-lipoxygenase Inhibitors Based on 2-[(4,6-Diphenethoxypyrimidin-2-yl-)thio]hexanoic Acid
Discovery and Biological Evaluation of a Novel Class of Dual Microsomal Prostaglandin E2 Synthase-1/5-lipoxygenase Inhibitors Based on 2-[(4,6-Diphenethoxypyrimidin-2-yl-)thio]hexanoic Acid
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DOI：
10.1021/jm200092b
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发表时间：
2011-07-14
影响因子：
7.3
通讯作者：
Werz, Oliver
中科院分区：
文献类型：
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作者：
Hieke, Martina;Greiner, Christine;Werz, Oliver
各种炎性疾病与白三烯（LT）和白藜芦醇（PG）的过度形成有关。在此，我们提出了一种新型的5-脂氧合酶（5-LO）和微粒体前列腺素E-2合酶-1（mPGES-1）的双重抑制剂，这两种酶分别是LT和PGE（2）形成的关键酶。根据2-[（4，6-二苯乙氧基嘧啶-2-基-）硫代]己酸（1）的结构，我们进行了详细的SAR分析，并进行了机理研究，以阐明5-LO抑制模式。有趣的是，包括1的硫醚的嘧啶环可以被简单的苄基或亚苄基部分取代，产生一系列新的生物活性2-亚苄基-和2-苄基己酸，例如2-（2，3-二苯基乙氧基亚苄基）己酸，29（IC 50 5-LO = 0.8 μ M; mPGES-1 = 1.1 μ M）。重要的是，没有一种新的生物活性衍生物强烈抑制环氧合酶活性。总之，我们提供了新的有前途的先导化合物，用于治疗炎症性疾病的价值，在体内进一步调查。
Various inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E-2 synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of the structure of 2-[(4,6-diphenethoxypyrimidin-2-yl-)thio]hexanoic acid (1), we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition. Interestingly, the pyrimidine ring including the thioether of 1 could be replaced by a simple benzyl or a benzylidene moiety yielding a novel series of bioactive 2-benzylidene- and 2-benzylhexanoic acids exemplified by 2-(2,3-diphenethoxybenzylidene)hexanoic acid, 29 (IC50 5-LO = 0.8 mu M; mPGES-1 = 1.1 mu M). Importantly, none of the novel bioactive derivatives strongly inhibited cyclooxygenase activities. Together, we provide novel promising lead compounds for the treatment of inflammatory diseases valuable for further investigations in vivo.