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Nettekoven, Matthias; Adam, Jean‐Michel; Bendels, Stefanie; Bissantz, Catarina; Fingerle, Jürgen; Grether, Uwe; Grüner, Sabine; Guba, Wolfgang; Kimbara, Atsushi; Ottaviani, Giorgio; Püllmann, Bernd; Rogers‐Evans, Mark; Röver, Stephan; Rothenhäusler, Benno; Schmitt, Sebastien; Schuler, Franz; Schulz‐Gasch, Tanja; Ullmer, Christoph

Novel Triazolopyrimidine‐Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases

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  • Medientyp: E-Artikel
  • Titel: Novel Triazolopyrimidine‐Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases
  • Beteiligte: Nettekoven, Matthias; Adam, Jean‐Michel; Bendels, Stefanie; Bissantz, Catarina; Fingerle, Jürgen; Grether, Uwe; Grüner, Sabine; Guba, Wolfgang; Kimbara, Atsushi; Ottaviani, Giorgio; Püllmann, Bernd; Rogers‐Evans, Mark; Röver, Stephan; Rothenhäusler, Benno; Schmitt, Sebastien; Schuler, Franz; Schulz‐Gasch, Tanja; Ullmer, Christoph
  • Erschienen: Wiley, 2016
  • Erschienen in: ChemMedChem
  • Sprache: Englisch
  • DOI: 10.1002/cmdc.201500218
  • ISSN: 1860-7179; 1860-7187
  • Schlagwörter: Organic Chemistry ; General Pharmacology, Toxicology and Pharmaceutics ; Molecular Medicine ; Drug Discovery ; Biochemistry ; Pharmacology
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>The cannabinoid receptor 2 (CB2) system is described to modulate various pathological conditions, including inflammation and fibrosis. A series of new heterocyclic small‐molecule CB2 receptor agonists were identified from a high‐throughput screen. Lead optimization gave access to novel, highly potent, and selective (over CB1) triazolopyrimidine derivatives. A preliminary structure–activity relationship was established, and physicochemical properties in this compound class were significantly improved toward better solubility, lipophilicity, and microsomal stability. An optimized triazolopyrimidine derivative, (3<jats:italic>S</jats:italic>)‐1‐[5‐<jats:italic>tert</jats:italic>‐butyl‐3‐[(1‐cyclopropyltetrazol‐5‐yl)methyl]triazolo[4,5‐<jats:italic>d</jats:italic>]pyrimidin‐7‐yl]pyrrolidin‐3‐ol (<jats:bold>39</jats:bold>), was tested in a kidney ischemia–reperfusion model, in which it showed efficacy at a dose of 10 mg kg<jats:sup>−1</jats:sup> (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound <jats:bold>39</jats:bold> was also protective in a model of renal fibrosis. Oral treatment with <jats:bold>39</jats:bold> at 3 mg kg<jats:sup>−1</jats:sup> per day significantly decreased the amount of fibrosis by ∼40 % which was induced by unilateral ureter obstruction.</jats:p>