2. Academic Validation
  3. Novel thiazolopyridine derivatives of diflapolin as dual sEH/FLAP inhibitors with improved solubility

Novel thiazolopyridine derivatives of diflapolin as dual sEH/FLAP inhibitors with improved solubility

  • Bioorg Chem. 2023 Oct:139:106685. doi: 10.1016/j.bioorg.2023.106685.
Martin Schoenthaler 1,  Lorenz Waltl 2,  Thomas Hasenoehrl 1,  David Seher 1,  Anna Lutz 3,  Lucia Aulinger 3,  Veronika Temml 4,  Stefanie König 5,  Anita Siller 6,  Doris Elfriede Braun 7,  Ulrike Garscha 5,  Oliver Werz 8,  Daniela Schuster 4,  Harald Schennach 6,  Andreas Koeberle 9,  Barbara Matuszczak 10
Affiliations

Affiliations

  • 1 Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
  • 2 Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Mitterweg 24, A-6020 Innsbruck, Austria.
  • 3 Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria; Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Mitterweg 24, A-6020 Innsbruck, Austria.
  • 4 Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical University Salzburg, Strubergasse 21, A-5020 Salzburg, Austria.
  • 5 Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry, University of Greifswald, Friedrich-Ludwig-Jahn-Straße 17, D-17489 Greifswald, Germany.
  • 6 Central Institute for Blood Transfusion and Immunology, Tirol Kliniken GmbH, Anichstraße 35, A-6020 Innsbruck, Austria.
  • 7 Institute of Pharmacy, Department of Pharmaceutical Technology, Josef-Moeller-Haus, University of Innsbruck, Innrain 52c, A-6020 Innsbruck, Austria.
  • 8 Department of Pharmaceutical/Medicinal Chemistry, Friedrich Schiller University Jena, Philosophenweg 14, D-07743 Jena, Germany.
  • 9 Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Mitterweg 24, A-6020 Innsbruck, Austria. Electronic address: andreas.koeberle@uibk.ac.at.
  • 10 Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. Electronic address: barbara.matuszczak@uibk.ac.at.
PMID: 37418786 DOI: 10.1016/j.bioorg.2023.106685
Abstract

Inflammatory responses are orchestrated by a plethora of lipid mediators, and perturbations of their biosynthesis or degradation hinder resolution and lead to uncontrolled inflammation, which contributes to diverse pathologies. Small molecules that induce a switch from pro-inflammatory to anti-inflammatory lipid mediators are considered valuable for the treatment of chronic inflammatory diseases. Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) are afflicted with side effects caused by the inhibition of beneficial prostanoid formation and redirection of arachidonic acid (AA) into alternative pathways. Multi-target inhibitors like diflapolin, the first dual inhibitor of soluble Epoxide Hydrolase (sEH) and 5-lipoxygenase-activating protein (FLAP), promise improved efficacy and safety but are confronted by poor solubility and bioavailability. Four series of derivatives bearing isomeric thiazolopyridines as bioisosteric replacement of the benzothiazole core and two series additionally containing mono- or diaza-isosteres of the phenylene spacer were designed and synthesized to improve solubility. The combination of thiazolo[5,4-b]pyridine, a pyridinylen spacer and a 3,5-Cl2-substituted terminal phenyl ring (46a) enhances solubility and FLAP antagonism, while preserving sEH inhibition. Moreover, the thiazolo[4,5-c]pyridine derivative 41b, although being a less potent sEH/FLAP Inhibitor, additionally decreases thromboxane production in activated human peripheral blood mononuclear cells. We conclude that the introduction of nitrogen, depending on the position, not only enhances solubility and FLAP antagonism (46a), but also represents a valid strategy to expand the scope of application towards inhibition of thromboxane biosynthesis.

Keywords

5-lipoxygenase-activating protein (FLAP); Diflapolin; Dual inhibitor; Inflammation; Soluble epoxide hydrolase (sEH).

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