Structure鈥揂ctivity Relationship of Nonacidic Quinazolinone Inhibitors of Human Microsomal Prostaglandin Synthase 1 (mPGES聽1)

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• 作者：Florian R枚rsch ; Estel.la Buscat贸 ; Klaus Deckmann ; Gisbert Schneider ; Manfred Schubert-Zsilavecz ; Gerd Geisslinger ; Ewgenij Proschak ; Sabine Gr枚sch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3792-3803
• 全文大小：517K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

Microsomal prostaglandin E synthase 1 (mPGES-1) is a key enzyme of the arachidonic acid cascade. Its product PGE₂ plays an important role in various inflammatory processes, pain, fever, and cancer. Selective inhibition of mPGES-1 might be a promising step to avoid cyclooxygenase-related effects of NSAIDs. We studied a class of quinazolinone derivatives of the lead structure FR20 for their effects on the isolated human and murine enzymes, human HeLa cells, and in various settings of the whole blood assay. Novel compounds with direct enzyme inhibiting activity in the submicromolar range (IC₅₀: 0.13鈥?.37 渭M) were designed using a bioisosteric replacement strategy and proved to be effective in both cells and human whole blood. Furthermore, pharmacological profiling of toxicity and eicosanoid screening with LC/MS-MS was applied to characterize this new class of mPGES-1 inhibitors.