Structure-Based Discovery of Inhibitors of Microsomal Prostaglandin E2 Synthase鈭?, 5-Lipoxygenase and 5-Lipoxygenase-Activating Protein: Promising Hits for the Development of New Anti-infla

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• 作者：Rosa De Simone ; Maria Giovanna Chini ; Ines Bruno ; Raffaele Riccio ; Daniela Mueller ; Oliver Werz ; Giuseppe Bifulco
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 24, 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1565-1575
• 全文大小：1161K
• 年卷期：v.54,no.6(March 24, 2011)
• ISSN：1520-4804

文摘

Microsomal prostaglandin E₂ synthase (mPGES)-1 catalyzes the transformation of PGH₂ to PGE₂ that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC₅₀ value of 3.2 渭M, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC₅₀ = 0.4 渭M).