1. Novel Triazolopyrimidine-Derived Cannabinoid Receptor 2 Agonists as Potential Treatment for Inflammatory Kidney Diseases
- Author
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Sebastien Schmitt, Giorgio Ottaviani, Bernd Püllmann, Catarina Bissantz, Atsushi Kimbara, Sabine Grüner, Jean-Michel Adam, Benno Rothenhäusler, Matthias Nettekoven, Jürgen Fingerle, Wolfgang Guba, Franz Schuler, Tanja Schulz-Gasch, Stephan Röver, Stefanie Bendels, Mark Rogers-Evans, Christoph Ullmer, and Uwe Grether
- Subjects
Models, Molecular ,0301 basic medicine ,medicine.medical_specialty ,Cannabinoid receptor ,Inflammation ,Pharmacology ,Biochemistry ,Receptor, Cannabinoid, CB2 ,Structure-Activity Relationship ,03 medical and health sciences ,Fibrosis ,Internal medicine ,Drug Discovery ,medicine ,Renal fibrosis ,Cannabinoid receptor type 2 ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Cannabinoid Receptor Agonists ,Kidney ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Organic Chemistry ,Triazoles ,medicine.disease ,Pyrimidines ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Lipophilicity ,Molecular Medicine ,Kidney Diseases ,medicine.symptom - Abstract
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, (3S)-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.
- Published
- 2015
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