Novel and Potent Inhibitors of 5-Lipoxygenase Product Synthesis Based on the Structure of Pirinixic Acid

作者：Oliver Werz, Christine Greiner, Andreas Koeberle, Christina Hoernig, Sven George, Laura Nicoleta Popescu, Ivonne Syha, Manfred Schubert‐Zsilavecz, Dieter Steinhilber · 发表于：Journal of Medicinal Chemistry · 年份：2008 · DOI：10.1021/jm800588x · 被引用次数：24 · 研究领域：Synthesis and biological activity、Synthesis and Biological Evaluation、Synthesis of heterocyclic compounds

A novel class of potent 5-lipoxygenase (5-LO) product synthesis inhibitors based on the structure of pirinixic acid (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid, compound 1) is presented. Systematic profiling of 1, i.e., esterification of the carboxylic acid, alpha-substitution, and replacement of the o-dimethylaniline by 6-aminoquinoline, leads to potent suppressors of 5-LO product formation in activated polymorphonuclear leukocytes, exemplified by ethyl 2-[4-chloro-6-(quinoline-6-ylamino)-pyrimidin-2-ylsulfanyl]octane-1-carboxylate (6d, IC50 = 0.6 microM). These derivatives may possess potential for intervention with inflammatory and allergic diseases.