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Research ArticleInflammation, Immunopharmacology, and Asthma

Tandem Benzophenone Amino Pyridines, Potent and Selective Inhibitors of Human Leukotriene C4 Synthase

Thea K. Kleinschmidt, Martin Haraldsson, Devaraj Basavarajappa, Erik Lundeberg, Madhuranayaki Thulasingam, Maria Ekoff, Alexander Fauland, Christoph Lehmann, Astrid S. Kahnt, Lennart Lindbom and Jesper Z. Haeggström
Journal of Pharmacology and Experimental Therapeutics October 2015, 355 (1) 108-116; DOI: https://doi.org/10.1124/jpet.115.227157
Thea K. Kleinschmidt
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Martin Haraldsson
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Devaraj Basavarajappa
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Erik Lundeberg
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Madhuranayaki Thulasingam
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Maria Ekoff
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Alexander Fauland
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Christoph Lehmann
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Astrid S. Kahnt
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Lennart Lindbom
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Jesper Z. Haeggström
Department of Medical Biochemistry and Biophysics (T.K.K., D.B., M.T., A.F., J.Z.H.) and Chemical Biology Consortium Sweden, Science for Life Laboratory Stockholm, Department of Medical Biochemistry and Biophysics (M.H.), and Microvascular Physiology Research Group, Department of Physiology and Pharmacology (E.L., L.L.), Karolinska Institutet, Stockholm Sweden; Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden (M.E.); and Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt/Main, Germany (C.L., A.S.K.)
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Abstract

Cysteinyl leukotrienes (cys-LTs) are lipid mediators of inflammation. The enzyme catalyzing synthesis of cys-LTs, leukotriene C4 synthase (LTC4S), is considered an important drug target. Here we report the synthesis and characterization of three tandem benzophenone amino pyridines as inhibitors of LTC4S in vitro and in vivo. The inhibitors were characterized in vitro using recombinant human LTC4S, MonoMac 6 cells, and a panel of peripheral human immune cells. In vivo, the compounds were tested in the Zymosan A-induced peritonitis mouse model. The molecules, denoted TK04, TK04a, and TK05, were potent and selective inhibitors of LTC4S with IC50 values of 116, 124, and 95 nM, respectively. Molecular docking revealed binding in a hydrophobic crevice between two enzyme monomers and interaction with two catalytic residues, Arg104 and Arg31. The TK compounds potently inhibited cys-LT biosynthesis in immune cells. In coincubations of platelets and polymorphonuclear leukocytes, inhibition of LTC4S led to shunting of LTA4 toward anti-inflammatory lipoxin A4, which was significantly enhanced by simultaneous inhibition of LTA4H. Finally, we found that TK05 (6 mg⋅kg−1⋅body weight) reduces LTE4 levels in peritoneal lavage fluid by 88% and significantly decreases vascular permeability in vivo. Our findings indicate that the TK compounds are valuable experimental tools in eicosanoid research in vitro and in vivo. Their chemical structures may serve as leads for further inhibitor design. Novel drugs depleting cys-LT production could be beneficial for treatment of inflammatory diseases associated with overexpression of LTC4S.

Footnotes

    • Received July 7, 2015.
    • Accepted August 12, 2015.
  • We acknowledge the financial support of the Else Kröner-Fresenius-Graduiertenkolleg funded by the Else Kröner-Fresenius Stiftung, the LOEWE initiative Anwendungsorientierte Arzneimittelforschung, and Fraunhofer IME-TMP, as well as the Lars Hierta Memorial foundation. This study was supported by the Swedish Research Council [10350, 20854 Linneus Grant CERIC], the Cardiovascular Program, and Thematic Center for Inflammation. J.Z.H. is supported by a Distinguished Professor Award from Karolinska Institutet.

  • dx.doi.org/10.1124/jpet.115.227157

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 1
1 Oct 2015
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Research ArticleInflammation, Immunopharmacology, and Asthma

Potent and Selective Inhibitors of Human LTC4S

Thea K. Kleinschmidt, Martin Haraldsson, Devaraj Basavarajappa, Erik Lundeberg, Madhuranayaki Thulasingam, Maria Ekoff, Alexander Fauland, Christoph Lehmann, Astrid S. Kahnt, Lennart Lindbom and Jesper Z. Haeggström
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 108-116; DOI: https://doi.org/10.1124/jpet.115.227157

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Research ArticleInflammation, Immunopharmacology, and Asthma

Potent and Selective Inhibitors of Human LTC4S

Thea K. Kleinschmidt, Martin Haraldsson, Devaraj Basavarajappa, Erik Lundeberg, Madhuranayaki Thulasingam, Maria Ekoff, Alexander Fauland, Christoph Lehmann, Astrid S. Kahnt, Lennart Lindbom and Jesper Z. Haeggström
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 108-116; DOI: https://doi.org/10.1124/jpet.115.227157
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