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Novel Triazolopyrimidine‐Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases
Author(s) -
Nettekoven Matthias,
Adam JeanMichel,
Bendels Stefanie,
Bissantz Catarina,
Fingerle Jürgen,
Grether Uwe,
Grüner Sabine,
Guba Wolfgang,
Kimbara Atsushi,
Ottaviani Giorgio,
Püllmann Bernd,
RogersEvans Mark,
Röver Stephan,
Rothenhäusler Benno,
Schmitt Sebastien,
Schuler Franz,
SchulzGasch Tanja,
Ullmer Christoph
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500218
Subject(s) - cannabinoid receptor type 2 , kidney , cannabinoid , chemistry , fibrosis , cannabinoid receptor , pharmacology , receptor , inflammation , agonist , medicine , biochemistry
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 S )‐1‐[5‐ tert ‐butyl‐3‐[(1‐cyclopropyltetrazol‐5‐yl)methyl]triazolo[4,5‐ d ]pyrimidin‐7‐yl]pyrrolidin‐3‐ol ( 39 ), was tested in a kidney ischemia–reperfusion model, in which it showed efficacy at a dose of 10 mg kg −1 (p.o.). A significant depletion of the three measured kidney markers indicated a protective role of CB2 receptor activation toward inflammatory kidney damage. Compound 39 was also protective in a model of renal fibrosis. Oral treatment with 39 at 3 mg kg −1 per day significantly decreased the amount of fibrosis by ∼40 % which was induced by unilateral ureter obstruction.