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Structure–Activity Relationship of Nonacidic Quinazolinone Inhibitors of Human Microsomal Prostaglandin Synthase 1 (mPGES 1)

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    Structure–Activity Relationship of Nonacidic Quinazolinone Inhibitors of Human Microsomal Prostaglandin Synthase 1 (mPGES 1)
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    † Johann Wolfgang Goethe-University, Institute of Clinical Pharmacology, pharmazentrum frankfurt, LiFF/ZAFES, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
    ‡ Johann Wolfgang Goethe-University, Institute of Pharmaceutical Chemistry, LiFF/ZAFES, Max-von-Laue-Strasse 9, D-60438 Frankfurt/Main, Germany
    § ETH Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland
    *Phone: +49 69 6301 6086. Fax: +49 69 6301 7636. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2012, 55, 8, 3792–3803
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    https://doi.org/10.1021/jm201687d
    Published March 26, 2012
    Copyright © 2012 American Chemical Society
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    Abstract

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    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: 0.13–0.37 μM) 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.

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    IC50 dose–response curve of compound 7. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 48 publications.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2012, 55, 8, 3792–3803
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm201687d
    Published March 26, 2012
    Copyright © 2012 American Chemical Society
    Request reuse permissions

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