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, Jesper Z. Haeggström

Research output: Contribution to journalArticleResearchpeer-review

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, MonoMac6 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.

LanguageEnglish
Pages108-116
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume355
Issue number1
DOIs
Publication statusPublished - 1 Oct 2015
Externally publishedYes

Fingerprint

Pyridines
Leukotriene A4
Leukotriene E4
Peritoneal Lavage
Inflammation Mediators
Zymosan
Eicosanoids
Ascitic Fluid
Capillary Permeability
Enzymes
Peritonitis
Pharmaceutical Preparations
Inhibitory Concentration 50
benzophenone
leukotriene-C4 synthase
Neutrophils
Anti-Inflammatory Agents
Blood Platelets
Body Weight
Lipids

Cite this

Kleinschmidt, Thea K. ; Haraldsson, Martin ; Basavarajappa, Devaraj ; Lundeberg, Erik ; Thulasingam, Madhuranayaki ; Ekoff, Maria ; Fauland, Alexander ; Lehmann, Christoph ; Kahnt, Astrid S. ; Lindbom, Lennart ; Haeggström, Jesper Z. / Tandem benzophenone amino pyridines, potent and selective inhibitors of human leukotriene C4 synthase. In: Journal of Pharmacology and Experimental Therapeutics. 2015 ; Vol. 355, No. 1. pp. 108-116.
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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, MonoMac6 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.",
author = "Kleinschmidt, {Thea K.} and Martin Haraldsson and Devaraj Basavarajappa and Erik Lundeberg and Madhuranayaki Thulasingam and Maria Ekoff and Alexander Fauland and Christoph Lehmann and Kahnt, {Astrid S.} and Lennart Lindbom and Haeggstr{\"o}m, {Jesper Z.}",
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Kleinschmidt, TK, Haraldsson, M, Basavarajappa, D, Lundeberg, E, Thulasingam, M, Ekoff, M, Fauland, A, Lehmann, C, Kahnt, AS, Lindbom, L & Haeggström, JZ 2015, 'Tandem benzophenone amino pyridines, potent and selective inhibitors of human leukotriene C4 synthase', Journal of Pharmacology and Experimental Therapeutics, vol. 355, no. 1, pp. 108-116. https://doi.org/10.1124/jpet.115.227157

Tandem benzophenone amino pyridines, potent and selective inhibitors of human leukotriene C4 synthase. / Kleinschmidt, Thea K.; Haraldsson, Martin; Basavarajappa, Devaraj; Lundeberg, Erik; Thulasingam, Madhuranayaki; Ekoff, Maria; Fauland, Alexander; Lehmann, Christoph; Kahnt, Astrid S.; Lindbom, Lennart; Haeggström, Jesper Z.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 355, No. 1, 01.10.2015, p. 108-116.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Tandem benzophenone amino pyridines, potent and selective inhibitors of human leukotriene C4 synthase

AU - Kleinschmidt, Thea K.

AU - Haraldsson, Martin

AU - Basavarajappa, Devaraj

AU - Lundeberg, Erik

AU - Thulasingam, Madhuranayaki

AU - Ekoff, Maria

AU - Fauland, Alexander

AU - Lehmann, Christoph

AU - Kahnt, Astrid S.

AU - Lindbom, Lennart

AU - Haeggström, Jesper Z.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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, MonoMac6 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.

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