Cyclooxygenase-2 Inhibitors. 1,5-Diarylpyrrol-3-acetic Esters with Enhanced Inhibitory Activity toward Cyclooxygenase-2 and Improved Cyclooxygenase-2/Cyclooxygenase-1 Selectivity

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• 作者：Mariangela Biava ; Giulio Cesare Porretta ; Giovanna Poce ; Sibilla Supino ; Stefano Forli ; Michele Rovini ; Andrea Cappelli ; Fabrizio Manetti ; Maurizio Botta ; Lidia Sautebin ; Antonietta Rossi ; Carlo Pergo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 1, 2007
• 年：2007
• 卷：50
• 期：22
• 页码：5403 - 5411
• 全文大小：148K
• 年卷期：v.50,no.22(November 1, 2007)
• ISSN：1520-4804

文摘

The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effectlimitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based onalternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives,along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selectiveCOX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, wedescribe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitoryeffects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3-acetate (1d), which was the most potent and COX-2 selective compound, alsoshowed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations fordeveloping new lead compounds that could be effective agents in the armamentarium for the managementof inflammation and pain.