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Research Article

Development of novel aminothiazole-comprising 5-LO inhibitors

    Simon B M Kretschmer‡

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany

    ‡Authors contributed equally

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    ,
    Stefano Woltersdorf‡

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany

    ‡Authors contributed equally

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    ,
    Carmen B Rödl

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany

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    ,
    Dominik Vogt

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany

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    ,
    Ann-Kathrin Häfner

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany

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    ,
    Dieter Steinhilber

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany

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    ,
    Holger Stark

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany

    Institute of Pharmaceutical & Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany

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    &
    Bettina Hofmann

    *Author for correspondence:

    E-mail Address: hofmann@pharmchem.uni-frankfurt.de

    Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt, Germany

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    Published Online:29 Jan 2016https://doi.org/10.4155/fmc.15.174

    Abstract

    Background: Leukotrienes are pivotal lipid mediators in various immune and inflammatory reactions. Herein, 5-LO is a validated target. 2-Aminothiazoles, as a privileged structure, implicate known 5-LO inhibitors like ST-1083 (IC50 [polymorphonuclear leukocytes (PMNL)] = 0.68 μM), yet deep structure–activity relationships (SAR) have not been established. Materials & methods: Compounds were synthesized via Hantzsch thiazole synthesis. Inhibitory activities were evaluated using intact PMNL and purified 5-LO together with cytotoxicity measurements in U937 cells. Results: We introduced novel functionalities at 2-, 3-, 4- and 5-position of the 2-aminothiazole scaffold and conducted bioisosteric replacement to optimize the parent scaffold. SARs of the 2-aminothiazole scaffold were deduced and extended primarily for inhibition of the 5-LO enzyme. Conclusion: SAR studies provided at least two optimized leads (ST-1853, ST-1906) with high potency (IC50 [polymorphonuclear leukocytes] = 0.05 μM), specificity and noncytotoxic behavior.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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