Design and synthesis of a second series of triazole-based compounds as potent dual mPGES-1 and 5-lipoxygenase inhibitors
Design and synthesis of a second series of triazole-based compounds as potent dual mPGES-1 and 5-lipoxygenase inhibitors
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DOI：
10.1016/j.ejmech.2012.05.014
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发表时间：
2012-08-01
影响因子：
6.7
通讯作者：
Bifulco, Giuseppe
中科院分区：
文献类型：
--
作者：
Chini, Maria Giovanna;De Simone, Rosa;Bifulco, Giuseppe
微粒体前列腺素E-2合酶（mPGES）-1和5-脂氧合酶（5-LO）分别是促炎性PGE（2）和白三烯生物合成的关键酶。描述了基于三唑骨架的第二系列mPGES-1抑制剂的设计和合成。我们的研究使我们能够绘制试验性SAR曲线，并通过鉴定在无细胞测定中显示有效mPGES-1抑制的化合物10、11和14-15来优化该系列。此外，化合物5、10、12和14-16还在无细胞和基于细胞的测试系统中阻断5-LO活性，成为开发更安全和更有效的抗炎药物的非常有前途的候选物。(C)2012年Elsevier Masson SAS。All rights reserved.
Microsomal prostaglandin E-2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO) are pivotal enzymes in the biosynthesis of the pro-inflammatory PGE(2) and leukotrienes, respectively. The design and synthesis of a second series of mPGES-1 inhibitors based on a triazole scaffold are described. Our studies allowed us to draw a tentative SAR profile and to optimize this series with the identification of compounds 10, 11 and 14-15 which displayed potent mPGES-1 inhibition in a cell-free assay. In addition, compounds 5, 10, 12 and 14-16 also blocked 5-LO activity in cell-free and cell-based test systems, emerging as very promising candidates for the development of safer and more effective anti-inflammatory drugs. (C) 2012 Elsevier Masson SAS. All rights reserved.